Substituted 2-benzyl-benzofuran derivatives

ABSTRACT

The compounds are of the class of substituted 2-(2-(palkoxybenzyl)-3-benzofuranyl)-ethylamines and pharmaceutically acceptable acid addition salts thereof and have analgesic, antitussive and spasmolytic properties; useful intermediates in the syntheses thereof are the correspondingly substituted 2-(palkoxybenzyl)-3-hydroxy-2,3-dihydro-3-benzofuranacetic acid alkyl esters, 2-(p-alkoxybenzyl)-3-benzofuranacetic acid alkyl esters and 2-(p-alkoxybenzyl)-3-benzofuran ethanols; also provided are pharmaceutical compositions comprising said benzofuranylethylamines or pharmaceutical acceptable acid addition salts thereof and a pharmaceutical carrier as well as methods of producing analgesic and spasmolytic effects in a mammal comprising administering them.

United States Patent Primary Examiner-Alton D. Rollins Assistant Examiner-Joseph A. Narcavage Attorneys- Karl F. .lorda and Bruce M. Collins ABSTRACT: The compounds are of the class of substituted 2-[2-(p-alkoxybenzyl)-3-benzofuranyll-ethylamines and pharmaceutically acceptable acid addition salts thereof and have analgesic, antitussive and spasmolytic properties; useful intermediates in the syntheses thereof are the correspondingly substituted 2-(p-alkoxybenzyl)-3-hydroxy-2,3-dihydro-3- benzofuranacetic acid alkyl esters, 2-(p-alkoxybenzyI)-3- benzofuranacetic acid alkyl esters and 2-(p-alkoxybenzyl)-3- benzofuran ethanols; also provided are pharmaceutical compositions comprising said benzofuranyl-ethylamines or pharmaceutical acceptable acid addition salts thereof and a pharmaceutical carrier as well as methods of producing analgesic and spasmolytic effects in a mammal comprising administering them.

SUBSTITUTED Z-BENZYL-BENZOFURAN DERIVATIVES DETAILED DESCRIPTION The present invention relates to benzofuran derivatives and pharmaceutically acceptable acid addition salts thereof having analgesic, antitussive and musculotropic-spasmolytic properties. processes for the production of these compounds, as well as to pharmaceutical compositions and their use.

More particularly, the present invention relates to compounds of the formula R4 R1 CHzOH2-N I l M R1 orb-@041: (I)

wherein R is hydrogen, halogen up to and including the atomic number 35, methyl, ethyl, methoxy, ethoxy or nitro;

R is hydrogen, halogen up to and-including the atomic number 35, methyl, ethyl, methoxy or ethoxy;

R is alkyl having at most four carbon atoms; and each R and R independent of the other is alkyl having at most four carbon atoms, or together with the adjacent nitrogen form the l-pyrrolidinyl, piperidinoor morpholino group;

and the pharmaceutically acceptable acid addition salts thereof.

A preferred subclass are compounds of formula I wherein R is hydrogen or methyl;

R, is chloro, methyl or ethyl;

R is ethyl or isopropyl;

each of R and R independent of the other is ethyl or or together with the adjacent nitrogen form the l-pyrrolidinyl, piperidino or morpholino group; and the pharmaceutically acceptable acid addition salts thereof.

Typical members are the following compounds: I-[Z-[Q-(p-ethoxybenzyl )-5-methyl-3-benzofuranyl]-ethyl 1- pyrrolidine;

l-[ 2-[2-(p-ethoxybenzyl )-5,6-dimethyl-3-benzofuranyll-ethyl l-pyrrolidine; N,N-diethyl-2-(p-ethoxybenzyl)-6-methyl-3-benzofuranethylamine;

l[ 2-[ 2-( p-ethoxybenzyl )-5-methyl-3-benzofuranyl]-ethyl]- piperidine; 4-[2-[2-(p-isopropoxybenzyl)-5-methyl-3-benzofuranyl]- ethyll-morpholine;

l-[2-[2-( p-ethoxybenzyl)-5-chloro-3-benzofuranyl]-ethyl]- pyrrolidine; N,N-diethyl-2-(p-ethoxybenzyl)-5-methoxy-3-benzofuranethylamine; N,N-di-n-propyl-(p-ethoxybenzyl)-5-methyl-3-benzofuranethylamine;

l-[ 2-[ 2-( p-isopropoxybenzyl)-5-methyl-3-benzofuranyl]- ethyl) ]-piperidine; l-[2-[2-(p-isopropoxybenzyl)-5-methyl-3-benzofuranyl]- ethyll-pyrrolidine; y

l-[ 2-[ Z-(p-ethoxybenzyl) 6-methyl'3-benzofuranyl]-ethyl]- pyrrolidine; l-[2-[2-(p-ethoxybenzyl)-6 ethyl-3-benzofuranyl]-ethyl]-pyrrolidine; N,N'diethyl-2-(p-ethoxybenzyl)-5-chloro-3-benzofuranethylamine;

and the pharmaceutically acceptable acid addition salts thereof, particularly the hydrochlorides thereof.

Particular important intermediates in the syntheses of compounds of formula I are the compounds of formulas ll, V and V1.

The present invention concerns also pharmaceutical compositions comprising a compound of formula I and/or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutical carrier therefor.

The present invention concerns further methods of producing analgesic, antitussive and musculotrop-spasmolytic effects in mammals comprising administering to said mammals an effective amount of a compound of formula I and/or a pharmaceutically acceptable acid addition salt thereof.

In the compounds of formula I and in the appertaining intermediates R, and R as halogen up to and including the atomic number 35, can be fluorine, chlorine or bromine; R R and R as alkyl having at most four carbon atoms, can be for example the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl group.

The benzofuran derivatives of formula I and their acid addition salts are produced according to a first process by reacting a reactive-ester of a compound of formula ll,

CHr-CHz-OH ILCE H.

wherein R R and R have the meanings given under "Formula I, with a compound of Formula III (III) ganic acid.

Suitable as reactive esters of compounds of formula ll are,

e.g., sulfonic acid esters, such as the p-toluene sulfonic acid esters and the methane sulfonic acid esters, as well as hydrohalic acid esters such as, e.g., bromides and chlorides. E As reaction medium and simultaneously as acid-binding agent,

' an excess of the base to be reacted of formula [II can be used, whereby the reaction is preferably performed between 60 and 120, i.e., at the boiling temperature of the base or, optionally,

' also below this temperature or above and, in the latter case, in

a closed vessel. By using dimethylforrnamide as reaction medium and an excess of base as acid-binding agent, the reaction,

can be performed at room temperature to moderately elevated temperature. Furthermore, the reaction can be carried out, e.g., in ethanol, butanone and dioxane, preferably at their boiling point and using excess base of formula III or, e.g.,

also tertiary organic bases or inorganic, acid-binding substances, e.g., carbonates such as potassium carbonate.

Compounds of formula ll are produced in the following manner. 3(2l-i)-Benzofuranones of formula lVa, substituted 0 CHO-Q-Olts I IVa IVb

Bi (V) From the latter are obtained by dehydration, e.g., with dilute sulfuric acid immediately following the decomposition of the reaction mixture or by heating the isolated ester alone or optionally in the presence of a substance which splits off water, lower 2-(p-alkoxybenzyl)-3-benzofuranacetic acid alkyl esters of formula VI R1 0112-0 o-o-m 0 cmo m which, in their turn, are optionally hydrolyzed to the corresponding 2'(p-alltoxybenzyl)-3-benzofuranacetic acids of formula Vll.

R2 (VI) -cm--o-m o a, v

In formulas V, VI and VII.

R, represents an alkyl group with at most four carbon atoms, while R,, R, and R, have the meanings given under formula I The reduction of the esters of formula V] with complex hydrides such as, e.g., lithium aluminum hydride or diborane in ethereal solvents, yields the 2-(p-alkoxybenzyl)-3-benzofuranethanols of fonnula ll. 2-(p-Alkoxybenzyl)-3-(2H)- benzofuranones of formula N can also be prepared by internal condensation and ringclosing of lower (o-alkoxycarbom ylphenoxy)-acetic acid alkyl esters, optionally substituted according to the definitions of R, and R by means of sodium to sodium compounds of 3(2H)-oxo-2-benzofurancarboxylic acid alkyl esters which are subsequently reacted with lower palkoxybenzyl bromides or chlorides to give the conesponding 2-p-alkoxybenzyl-3(2H)-oxo-2-benzofurancarboxylic acid alkyl esters. The latter are saponified and decarboxalated by means of methanolic potassium hydroxide solution at boiling temperature to give compounds of formula IV.

According to a second process, compounds of formula I and their acid addition salts are produced by reducing a compound R r J V IL ZR CH2-Z-N/ R2 (VIII) wherein one of the symbols Z is a methylene group, and the other a carbonyl group, and

R is an alkyl group with at most three carbon atoms which can be bonded to R and R,, R,,' R, and R have the meanings given under formula I, either directly or after reaction with triethyloxonium fluoroborate, and, optionally, converting the benzofuran derivative obtained of formula I into an addition salt with an inorganic or organic acid.

The direct reduction of the compounds of formula VIII occurs, for example. by means of lithium aluminum hydride or diborane, which is either produced beforehand or is formed in situ, e.g., from potassium boron hydride and boron trifluoride etherate, in an etheral solvent such as tetrahydrofuran, diethyl ether, dibutyl ether or diethylene glycol dimethyl ether, at temperatures between ca. 20 and or at the boiling temperature of the stated solvent. Instead of reducing the compounds of formula VI]! directly, they can be optionally firstly reacted with triethyloxonium fluoroborate in organic solvents inert to the latter such as, e.g. methylene chloride, to give the corresponding imonio-ethyl ester fluoroborates, e.g., those of partial formulas Yllla or Vlllb O-GHrH TCHz-C\ /R| 6131M 0 CzHs and these intermediate products are then reduced, e.g., either with an alkali metal boron hydride, such as potassium boron hydride, in a lower alkanol such as methanol, or with lithium aluminum hydride or diborane in an ethereal solvent.

Amides of 2-(p-alkoxybenzyl)-3-benzofuranacetic acids, falling under formula VI" can be produced for example from the corresponding lower alkyl esters of the carboxylic acids of formula VI, either in one stage by aminolysis with compounds of formula III, or in several stages by hydrolysis of the stated esters, transformation of the obtained carboxylic acids into reactive functional derivatives, such as chlorides, bromides or mixed anhydrides, and reaction of these derivatives with compounds of formula lll. Further starting materials of the formula VIII are, e.g., the 2-(p alkoxybenzyl)-3-[2-( N-alkylalkanamide)-alkyl]-benzofurans, optionally substituted according to the definition for R and R, and also compounds in which the radical R is independent of R or bonded with R,,, as for example, 2-( p-alkoxybenzyl )-3-[ 2-( 2-oxol -pyrrolidinyl )-alkyl]-benzofurans.

Suchlike starting materials can be prepared for example, by acylating secondary amines of the formula lXa,

wherein R, is hydrogen or an alkyl group with at most four carbon atoms, and

R,, R and R have the meaning given under formula I, with a lower oxoalkane under reducing conditions, or with a reactive ester of a lower alkanol in the presence of an acid-binding agent and, in each case, at least in the molar ratio corresponding to the number of hydrogen atoms to be replaced which are bound to the nitrogen atom or, if R, is hydrogen, also with a reactive ester of the l,4-butanediol, 1,5-pentanediol or diethylene glycol in the presence of an acid-binding agent and, optionally, converting the obtained benzofuran derivative of formula 1 into an addition salt with an inorganic or organic acid.

For the reaction with a lower oxoalkane such as, e.g., formaldehyde or acetaldehyde under reducing conditions, hydrogen at normal or moderately elevated pressures and temperatures is allowed to act, e.g., on a solution of starting material of formula IX wherein R, does not represent the nitro group, and oxoalkane in a suitable organic solvent such as, e.g., ethanol or dioxane, in the presence of a hydrogenation catalyst such as, e.g., Raney nickel, platinum oxide or palladium charcoal. If a compound of the formula I, in which a methyl group is to be present as R or both as R, and R is produced by reaction with excess formaldehyde, formic acid can also be used as a reducing reaction medium, at moderately elevated temperature to boiling temperature.

As reactive esters of lower alkanols or reactive diesters of the 1,4-butanediol, 1,5-pentanediol or diethylene glycol, halides or dihalides, especially bromides or dibromides are preferably used, also iodides or chlorides or diiodides or dichlorides. The reactions are performed hot, e.g., at the boiling temperature of the solvent used, e.g., in organic solvents such as, e.g., acetonitrile or methanol, or also without solvent in the presence of acid-binding agents such as, e.g., sodium or potassium carbonate, or in an excess of the compound to be reacted of formula IX.

Starting materials of formula IX having a hydrogen atom as radical R are produced, e.g., starting with 3(2l-I)-benzofuranon'es, optionally substituted corresponding to the definition for R, and R From the latter are firstly produced, by condensation with lower bromoacetic acid alkyl esters with zinc in benzene and subsequent dehydration, the corresponding lower 3-benzofuranacetic acid alkyl esters, the reduction of which with lithium aluminum hydride or diborane, e.g., in tetrahydrofuran, yields the corresponding 3-benzofuranethanols. These alcohols are converted into reactive esters, e.g., into p-toluene sulfonic acid esters or into chlorides or bromides and the latter are converted with ammonia into corresponding 3-benzofuran ethylamines. These amines are reacted with p-alkoxy-benzoyl chlorides in pyridine to give N- (p-alkoxybenzoyl)-derivatives, from which are obtained with the action of condensation agents, e.g., phosphorus pentoxide and phosphorus oxychloride in boiling toluene, with ring closure between amide group and 2-position of the benzofuran, 1-( p-alkoxyphenyl )-3 ,4-dihydro-benzofur-[ 2,3-c ]-pyridines, which are optionally substituted in the benzene nucleus corresponding to the definition of R, and R By reductive splitting of these tricycles by means of hydrazine, e.g., in the presence of sodium hydroxide in diethylene glycol at temperatures of about 200, compounds of the formula IX are finally obtained, i.e., 2-(p-alkoxybenzyl)-3-benzofuran ethylamines or derivatives thereof, substituted in the benzene nucleus corresponding to the definition for R, and R Further production possibility for the amines of formula I and also for such amines of formula IX, wherein R is a lower alkyl group, consists of the aminolysis of the above stated esters of formula VI with ammonia or lower alkylamines or also by the acylation of primary amines of formula IX, wherein R, is hydrogen, with an alkanoic acid chloride or anhydride to the corresponding secondary amides and subsequent reduction of the amides thus obtained with lithium aluminum hydride or diborane analogously to the second process mentioned for the production of the compounds of the formula 1. Compounds of formu- R,, R R R and R, have the meanings given under formula I,

i by means of a complex hydride in the presence of a Lewis acid in an ethereal solvent and, optionally, converting the obtained benzofuran derivative of formula I, into an addition salt with ,an inorganic or organic acid. For example, diborane in tetrahydrofuran, dibutyl ether or diethylene glycol dimethyl ether is allowed to act, at temperatures between 50 and or at the boiling temperature of the solvent, on a compound of formula X in the presence of boron trifluoride etherate; or to a solution of the starting material in the same reaction media is slowly added, in the presence of an excess of boron trifluoride etherate, the amount of lithium aluminum hydride or potassium boron hydride which is necessary for the reduction.

The starting materials of formula X are produced, for example, starting with 2-(p-alkoxybenzyl)-benzofurans, which can be substituted corresponding to the definition for R, and R by condensation with acetyl chloride according to the F riedel- Crafts reaction, e.g., with the aid of tin tetrachloride in carbon disulphide, subsequent bromination of the obtained 3-acetyl compounds to 3-bromoacetyl compounds and reaction of the latter with amines of formula III.

According to a fifth process, the benzofuran derivatives of formula I and their acid addition salts are produced by subjecting a compound of formula XI,

wherein R,, R R R and R, have the meanings given under formula I, to conditions under which water is split off and, optionally, converting the obtained benzofuran derivative of formula 1 into an addition salt with an inorganic or organic acid. By conditions under which water is split off is meant, e.g., either the treating of the compounds of formula XI with agents splitting off water, e.g., with strong acids such as p-toluene sulfonic acid, hydrochloric acid or sulfuric acid, in inert organic solvents at room temperature or at moderately elevated temperatures, e.g., around 80-120, or the heating of the compounds in the absence of agents splitting off water, but optionally in the presence of higher-boiling solvents to temperatures between ca. and 200.

The production of the starting materials of formula XI can be carried out starting with the above stated Reformatsky reaction products of formula V. Instead of dehydrating these hydroxy esters firstly to compounds of formula VI, they are reduced directly to the corresponding 2-(p-alkoxybenzyl)-3- hydroxy-2,3-dihydro-3-benzofuran ethanols. These are converted at low temperatures with p-toluenesulphochloride in pyridine, into their p toluenesulphonic acid esters. The starting materials of formula XI are obtained by reaction of the ptoluenesulphonic acid esters with compounds of formula III, analogously to the first process for the production of the benzofuran derivatives of formula I.

By the reaction of p-toluenesulphonic acid-2-[2-p-alkoxybenzyl)-2,3-dihydro-3hydroxy-3-benzofuranyl]-ethyl ester with amines of formula III, the thermal splitting off of water can occur from the firstly formed compounds of formula XI, wherein R, does not represent a halogen atom, to give directly, compounds of formula I.

According to a sixth process, the benzofuran derivatives of formula I and their acid addition salts are produced by reducing a compound of formula XII wherein R,, R R R and R have the meanings given under formula I by means of a complex hydride or hydrazine hydrate in the presence of an alkali metal hydroxide, and optionally converting the benzofuran derivative of formula I thus obtained into an addition salt thereof with an inorganic or organic acid.

For example, a compound of formula XII is allowed to react with diborane in tetrahydrofuran at room temperature or hydrazine hydrate in diethyleneglycol at a temperature of about 200.

The starting material of formula XII is obtained, for example, starting from alkanoic acid-2-(3-benzofuranylethyl-ester, which can be substituted according to the definitions given for R and R by reaction with p-alkoxybenzoyl chloride, e.g., using tin tetrachloride or titanium tetrachloride in carbon disulfide, saponification of the corresponding Z-(p-alkoxybenzoyl)-3-benzofuranethanols and subsequent reaction of the reactive esters themselves with amines of formula III;

According to a seventh process, benzofuran derivatives of formula I and their acid addition salts can be produced by reducing a compound of formula XIII wherein R,, R R R and R have the meanings given under formulal by means of a complex hydride and optionally converting the benzofuran derivative of formula I thus obtained into an addition salt thereof, with an inorganic or organic acid.

For example, a compound of formula XIII is allowed to react with a solution of diborane in e.g., tetrahydrofuran at room temperature or at slightly raised temperature.

The starting material of formula XIII is prepared, for example, starting from 3-benzofuran acetic acid alkyl esters, which can be substituted according to the definitions given for R, and R by reaction with p-alkoxybenzoyl chloride e.g., using tin tetrachloride or titanium tetrachloride in carbon disulfrde, to give 2-(p-alkoxybenzoyl)-3-benzofuran acetic acid alkyl esters, and aminolysis of the latter with an amine of formula III, optionally in the presence of a sufficient amount of methanol, for the esterification with a basic catalyst of the 2- (p-alkoxybenzoyl)-3-benzofuran acetic acid ethyl ester to the corresponding methyl ester at the boiling point of the amine or in a pressure vessel at a temperature of 80-130.

According to an eighth process benzofuran derivatives of formula la,

wherein R R and R; have the meanings given under formula I, with the exception of R being nitro, are prepared by reducing a compound of formula XIV e X 9 R1 CHCH2- Q R2 0 CHz-ORi (XIV) wherein R R and R have the meanings given under formula I, with the exception of R, being nitro, and

X@ is a monovalent anion or the normal equivalent of a polyvalent anion by means of catalytically activated hydrogen.

The hydrogenation can be carried out for example, in the presence of a platinum catalyst until the required amount-of hydrogen has been taken up.

The pyridinium compound of formula XIV required as starting material is prepared, for example, by the reaction of a reactive ester of a compound of formula II with pyridine at a slightly raised temperature. As reactive esters can be used e.g., the bromide or the p-toluene sulfonic acid ester.

It is to be understood that whenever an intermediate of the preset invention wherein R is nitro, is to be reduced, the reduction has to be carried out with an agent and under conditions whereby the nitro group will not be reduced simultaneously. Such an agent is for example diborane. The reducing conditions are for example refluxing in tetrahydrofuran. On the other hand whenever a reaction is to be carried out under conditions destroying the nitro group in the starting materials and the products of this reaction R as nitro is to be excepted.

Optionally, the benzofuran derivatives of formula I, obtained according to the invention are subsequently converted in the usual manner into their addition salts with inorganic and organic acids. For example, the acid desired as salt component, or a solution thereof, is added to a solution of a compound of formula I in an organic solvent such as acetone, dioxane, methanol or ethanol or diethyl ether, whereupon the salt is separated which precipitates directly or after addition of a second organic liquid such as, e.g., diethyl ether to acetone, or water to water-miscible solvents, such as acetone or dioxane.

Optionally, for use as active substances, for medicaments, it is possible to use instead of free bases, and preferably in solutions, pharmaceutically acceptable acid addition salts, i.e., salts with such acids, the anions of which, in the case of the dosages in question, have either no inherent pharmacological action or a desired one. Moreover, it is of advantage if the salts to be used as active substances crystallize wall and are not, or are only slightly, hygroscopic. For salt formation with compounds of formula I, it is possible to use, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanedisulfonic acid, B-hydroxyethanesulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, succinic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid or l,5-naphthalene disulfonic acid.

The useful pharmacological properties of the compounds of formula I are demonstrated in a number of well-known pharmacological tests.

The analgesic activity is demonstrated in the Hot-Plate Test according to A. O. Woolfe and G. McDonald, J. Pharmacol. Exptl. Therap. 80, 300(1944) using mice as experimental animals. In this test, for example the typical members of the compounds of formula I, particularly in form of their hydrochlorides, show a significant prolongation of the reaction time, i.e., an analgesic effect, on administration of about 100-200 mgJkg. of test compound per orally or about 10-25 mgjkg. intraperitoneally.

The analgesic their is further demonstrated in the Tail- Flick-Test according to H. Friebel and C. Reichle, Arch. exp. Path. and Pharmakol. 226, 551(1955), using mice as experimental animals. In this test, for example, the typical members of formula I, particularly in form of their hydrochlorides, show a significant prolongation of reaction time, i.e., an analgesic effect on administration of about 7-75 mg./kg. of test substance or about 1-20 mg./kg. intraperitoneally.

The antitussive activity of compounds of formula I and their pharmaceutically acceptable acid addition salts is demonstrated in cats according to the method of R. Domenjoz, Arch. exp. Path. and Phannakol. 215 19-24( 1952). Thus it is shown that, for example, the hydrochlorides of N,N-dimethyl-2-(pethoxybenzyl)-3-benzofuranethylamine, 4-[2-[2-(p-ethoxybenzyl)-3-benzofuranyl]-ethyl]-morpholine and of 4-[2-[2- (p-ethoxybenzyl)-5-methyl-3-benzofuranyl]-ethyl]- morpholine, on intravenous administration of about 2-5 mg./kg. of test substance, exhibit a significant antitussive activity.

The musculotropic-spasmolytic activity of compounds of formula I and their pharmaceutically acceptable salts is demonstrated with a test well known in the art, namely with the isolation intestine of the guinea pig, whereby the papaverine value is determined. The latter is a measure for the amount of test compound having an equally lytic effect as papaverine in counteracting the spasms produced by barium chloride. Thus it is shown that for example l-[2-[2-(p-ethoxybenzyl)-3-benzofuranyl]-ethyl]-pyrrolidine hydrochloride has a papaverine value of 0. 1. Similar activities are found with the typical members of the compounds of the invention mentioned above.

The pharmacologically active compounds of the invention have a favorable low toxicity and exhibit no depressant effect on the central nervous system. Their good compatibility in addition to above-described activities renders them suitable as active ingredients of pharmaceutical compositions for oral, rectal or parenteral administration for the relief and removal of conditions of pain of varying origin, including those of spasmodic nature, as well as tussive irritation.

For their intended use the new benzofuran derivatives of formula 1 and their phannaceutically acceptable acid addition salts are administered orally, rectally or parenterally in amounts depending on the species, and the age, weight and the particular condition of the individual being treated. For the treatment of conditions of pain in the case of mammals, daily dosages of 0.1-l mg./kg. (preferably 0.1-1.0 mg./kg.) are administered parentcrally and daily dosages of -100 mg./kg. (preferably 5-20 mg./kg.) orally or rectally. For the treatment of tussive irritation, the daily dosage orally or parentcrally, for warm-blooded animals is 0.252.5 mg./kg. Dosage units suitable for oral or rectal administration, such as drages', capsules, tablets or suppositories, preferably contain -100 mg., and ampuls preferably 5-25 mg. of a benzofuran derivative of formula I, or of a pharmaceutically acceptable salt thereof.

Dosage units for oral administration preferably contain as active substance between 5 and 90 percent of a pharmaceutically acceptable salt thereof. They are produced by combining the active substance, e.g., with solid pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols, to form tablets or drage cores. The latter are coated, e.g., with concentrated sugar solutions which can also contain, e.g., gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in readily volatile organic solvents or mixtures of so]- vents. Dyestuffs can be added to these coatings, e.g., to distinguish between varying dosages of active substance. Also suitaiii ble as oral dosage units are hard gelatine capsules as well as soft closed capsules made from gelatine and a softener, such as glycerin. The former preferably contain the active substance as a granulate in admixture with lubricants such as talcum or magnesium stearate and, optionally, stabilizers such as sodium metabisulfite or ascorbic acid. in soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as liquid polyethylene glycols, whereby stabilizers can likewise be added.

Also suitable for the treatment of coughing are, e.g., sucking tablets as well as oral preparations not administered in a single dosage such as, e.g., cough syrup and cough drops which are prepared with the usual auxiliary agents.

Suitable dosage units for rectal administration are, e.g., suppositories consisting of a combination of benzofuran derivative of formula I, or of a suitable salt thereof, with a neutral fatty base and, in addition, gelatine rectal capsules containing a combination of the active substance with polyethylene glycols.

Ampuls for parenteral, especially intramuscular and also intravenous administration, preferably contain a water-soluble salt of a benzofuran derivative of formula 1 as active substance in a concentration of preferably 0.5-5 percent, optionally together with suitable stabilizing agents and buffer substances in aqueous solution.

The following examples will serve to further typify the nature of the present invention; however, they should not be construed as a limitation on the scope thereof.

EXAMPLE 1 a. 40 g. of 5-methyl-3(2H)-benzofuranone [cp. K. Feist and E. Siebenlist, Arch. Pharm. 265, 196 (1927)] are dissolved in 35 ml. of hot absolute ethanol. To this solution are added 40.5 g. of p-ethoxybenzaldehyde and 2 ml. of concentrated hydrochloric acid and the solution is then refluxed for half an hour at boiling temperature. The acid addition produces a deep red coloration of the solution and an exothermic reaction. After a short time, the benzylidene compound commences to precipitate. After cooling, the reaction mixture is allowed to stand for ca. 15 hours at 0, whereupon the reaction product is filtered with suction and washed with a little ethanol. 54 g. (71.5 percent of theoretical amount) of 2-(pethoxybenzylidene)-5-methyl-3(2H)-benzofuranone are obtained as yellow needles, mp. 140-l42 after recrystallization form ethanol.

b. 38 g. of 2-(p-ethoxybenzylidene)-5-methyl-3(2H)- benzofuranone (in 700 ml. of dioxane) are added to 7 g. of prehydrogenated catalyst (5 percent palladium on barium carbonate) and hydrogenated at room temperature under normal pressure. After 5 hours, the hydrogen absorption of over percent of the theoretical value and the initially yellow solution is practically decolorized. As soon as no further hydrogen absorption occurs, the catalyst is removed by filtration and the filtrate concentrated by evaporation in vacuo. By crystallization of the residue from ether/petroleum ether are obtained 30 g. of 2-(p-ethoxybenzyl)-5-methyl-3(2H)-benzofuranone as yellowish crystals, m.p. 74.575, yield 75 percent of theoretical amount.

0. 17.0 g. of 2-(p-ethoxybenzyl)-5-methyl-3(2H)-benzofuranone and 43.0 g. of bromoacetic acid methyl ester are dissolved in 300 ml. of absolute benzene and slowly added dropwise, while vigorously stirring, to a mixture of 22 g. of zinc wool, 0.1 g. of mercury (ID-chloride and ml. of boiling benzene. Practically the whole of the zinc has dissolved after 3 hours. The reaction mixture is then refluxed at boiling temperature for a further 4 hours. lt is then cooled to room temperature and decomposed with 200 ml. of 2N sulfuric acid. To split off water from the stereoisomeric 2-(p-ethoxybenzyl)-3- hydroxy-3-benzofuranacetic acid methyl esters, the two-phase mixture is stirred until a specimen of the benzene phase exhibits only a main spot (Rf=ca. 0.8) in the thin-layer chromatogram (carrier=aluminum oxide neutral Merck, solvent llll benzene/ether (1:1 v/v), coloration by heating to 100 after spraying with 10 percent sulfuric acid in ethanol). The benzene layer is then taken 01?, washed neutral, dried over sodium sulfate and filtered through a chromatography column charged with 500 g. of neutral aluminum oxide Woelm activity degree 11!. Eluting of the partially absorbed reaction product with benzene and concentrating by evaporation of the extract combined with the filtrate yields 15.9 g. of 2-(p-eth0xybenzyl)-5-methyl-3-benzofuranacetic acid methyl ester as yellowish oil (yield 78 percent of theoretical value). The ester crystallizes from petroleum ether as colorless needles, m.p. 7071. A sample of the ester, refluxed with 1N potassium hydroxide solution in aqueous ethanol for 2 hours yields, after evaporating off the ethanol, acidifying with 2N sulfuric acid, extracting with ether and crystallizing from ether/petroleum ether, the corresponding acid m.p. l74-l75.

c'. 2.7 grams of 2-(p-ethoxybenzyl)-5-methyl-3(2H)- benzofuran are reacted analogously to example with 6.6 grams of bromoacetic acid methyl ester and 3.3 grams of zinc wool. 20 m1. of twice normal sulfuric acid are then added and the mixture is stirred for about 2 minutes. The benzene phase is washed neutral, dried over sodium sulfate and evaporated. The residual, 3.3. g., of oily raw product are chromatagraphed on 130 g. of neutral aluminum oxide Woelm Activity Stage lll. Fractions of each 100 ml. are taken according to the table shown below.

Residue after Fraction Solvent (V/V) The combined fractions 1 and 2 give from petrol ether 2.1 g. of 2-(p-ethoxybenzyl)-5-methyl-3-ben2ofuran acetic acid methyl ester, m.p. 70-71. From the combined fractions 7 and 8 is obtained, after crystallization from ether/petrol ether, 0.18 g. of racemic 2-(p-ethoxybenzyl)-5-methyl-2,3-dihydro- 3-hydroxy-3-benzofuran acetic acid methyl ester, M.P. 8l82 designated here as racemate B. The corresponding racemate A" is found in the fractions 5 and 6 as a colorless oil. (1R in CH C1 3,540 cm."Ol-l, 1,730 cmfCO.)

d. 3.6 g. of 2-(p-ethoxybenzyl)-5-methyl-3-benzofuranacetic acid methyl ester, dissolved in 10 ml. of absolute tetrahydrofuran, are added dropwise, while stirring, to a suspension of 1.5 g. of lithium aluminum hydride in 30 ml. of absolute tetrahydrofuran and the mixture is refluxed for 3 hours. The mixture is then cooled with ice and decomposed with dilute hydrochloric acid. After the addition of 10 ml. of a semisaturated solution of potassium sodium tartrate and neutralization with concentrated aqueous ammonia solution, the tetrahydrofuran is evaporated off in vacuo and the mixture, diluted with water, is repeatedly extracted with ether. The ether extracts, washed neutral and dried over sodium sulfate are filtered through 20 g. of neutral aluminum oxide of Woelm activity stage 111 and eluted with ether. Filtrate and extracts yield, after concentration by evaporation, 3.0 g. (91 percent of theoretical value) of 2-(p-ethoxybenzyl)-5-methyl- 3-benzofuranethanol as colorless oil.

e. 3.0 g. of the alcohol, obtained according to (d), are dissolved in 10 ml. of absolute pyridine and the solution is cooled to -l0. To this are added 5.0 g. of p-toluene sulfochloride in portions in such a manner that the temperature does not exceed 5. The mixture is allowed to stand for hours at 0, whereupon it is poured into ice water and the precipitated oil separated and triturated. Crystallization occurs after some time. Recrystallization from ether/petroleum ether yields 3.2

g. of p-toluenesulfonic acid-Z-[Z-(p-ethoxybenzyl)-5-methyl- 3-benzofuranyl1-ethyl ester, m.p. 7879 (yield 71 percent).

f. 2.3 g. of p-toluenesulfonic acid-2-[2-(p-ethoxybenzyl)-5- methyl-3-benzofuranyl]-ethylester with 10 ml. of pyrrolidine are refluxed for 4 hours. The reaction solution is then completely concentrated by evaporation in vacuo, 20 ml. of benzene are added and again it is completely concentrated by evaporation. The residue is taken up in water and ether. The ethereal phase is repeatedly washed with water and then extracted three times using 5 m1. of 1N hydrochloric acid each time. The acid extracts are adjusted with concentrated am monia to pH 9 and the hereby precipitated oily base is extracted with ether. The ethereal extract, washed with water, is dried over sodium sulfate and concentrated by evaporation in vacuo. The obtained crude l-[2-[2-(p-ethoxybenzyl)-5- methyl-3-benzofuranyl]-ethyl]-pyrrolidine is dissolved in ether and to the solution is added a slight excess of ethereal hydrochloric acid. The precipitated hydrochloride crystallizes upon triturating. After recrystallization from acetone/ether are obtained 1.6 g. of colorless crystals of the l-[2-[2-(pethoxybenzyl)-5-methyl-3-benzof1.|ranyl]-ethyl]-pyrrolidine hydrochloride, m.p. 167-169, yield 80 percent of theoretical value.

EXAMPLE 2 a. 2.3 g. of p-toluenesulfonic acid-2-[2-(p-ethoxybenzyl)-5- methyl-3-benzofuranyl]-ethyl ester [cp. example l(a)-(e)] are refluxed for 24 hours, while stirring, with 0.6 ml. of piperidine and 2.8 g. of potassium carbonate in 20 ml. of butanone. The inorganic salts are separated by filtration and the filtrate concentrated by evaporation in vacuo. The obtained crude l-[2-[2-(p-ethoxybenzyl)-5-methyl-3-benzofuranyl]- ethyll-piperidine is dissolved in ether and a slight excess of ethereal hydrogen chloride is added. The precipitated hydrochloride is separated and recrystallized from acetone. By this means are obtained 1.5 g. of l-[2-[2-( p-ethoxybenzyl)- 5-methyl-3-benzofuranyl]-ethyl]-piperidine hydrochloride, m.p. 192-193. Yield 73 percent of theoretical value.

b. The hydrogen oxalate melts at 2l4-2l5 with decomposition (from methanol/acetone).

c. in an analogous manner 0.60 g. of crude 5-methyl-2-(pethoxybenzyl)-3-benzofuranyl ethyl bromide are reacted with 0.15 ml. of pyrridine and 1.0 g. of potassium carbonate in 5 ml. of butanone. 1-[2-[2-(p-ethoxybenzyl)-5-methyl-3- benzofuranyl1-ethylIpiperidine hydrochloride, m.p. l92l9 3, is obtained after recrystallization from acetone 0.44 g. (yield 66 percent.) Similarly, with 0.15 ml. of pyrrolidine, l-[2 -[2-(p-ethoxybenzyl)-5-methyl-3-benzofuranyll-ethyl]-pyrrolidine hydrochloride is obtained, m.p. l67169 (yield 70 percent of theory).

The required starting material 5-methyl-2-(p-ethoxybenzyl)-3-benzofuranyl-ethyl bromide is prepared as follows;

0.56 g. of 5-methyl-2-(p-ethoxybenzyl)-3-benzofuranethanol are dissolved in 1.0 ml. of absolute pyrridine, the solution cooled to 15 and 0.15 ml. of thionyl bromide added. At this point a formation of precipitate and a rise of temperature to 2 is observed. After keeping this solution at 0 for 48 hours water is added, the precipitated oil taken up in ether and washed with l-hydrochloric acid and water. The ether phase is dried over sodium sulfate and evaporated. There remains 0.6 g. of crude 5-methyl-2-(p-ethoxybenzyl)-3- benzofuranyl-ethyl bromide, a yellow oil.

EXAMPLE 3 2.3 g. of p-toluenesulfonic acid-2-[2-(p-ethoxybenzyl)-5- methyl-3-benzofuranyl]-ethy1 ester [cp. example l(a)-(e)] are refluxed with 10 ml. of diethylamine for 48 hours. The reaction solution is then completely concentrated by evaporation in vacuo, 20 ml. of benzene are added and the solution is again completely concentrated by evaporation. The residue is taken up in water and ether. The ethereal phase is repeatedly washed with water and then extracted three times using 5 m1.

of 1N hydrochloric acid each time. The acid extracts are adjusted to pH 9 with concentrated ammonia and the thereby precipitated (oily) base is extracted with ether. The ethereal extract, washed with water, is dried over sodium sulfate and concentrated by evaporation in vacuo. The crude, residual, N,N-diethyl-2-(p-ethoxybenzyl)-5-methyl-3-benzofuranethylamine is dissolved in ether and a slight excess of ethereal hydrochloric acid is added. The precipitated hydrochloride is recrystallized from acetone/ether, whereby 1.5 g. of N,N- diethyl-Z-(p-ethoxybenzyl)--methyl-3-benzofuran ethylamine hydrochloride are obtained as colorless crystals, m.p. l39140. Yield 72 percent of theoretical value).

EXAMPLE 4 2.3 g. of p-toluenesulfonic acid-2-[2-(pethoxybenzyl-5- methyl-3-benzofuranyl1-ethyl ester [cp. example l(a)-(e)] are refluxed with ml. of morpholine for 4 hours. The reaction solution is then completely concentrated by evaporation in vacuo, 20 ml. of benzene are added and the solution is again completely concentrated by evaporation. The residue is taken up in water and ether. The ethereal phase is repeatedly washed with water and then extracted three times using 5 ml. of 1N hydrochloric acid each time. The acid extracts are adjusted to pH 9 with concentrated ammonia and the thereby precipitated (oily) base is extracted with ether. The ethereal extract, washed with water, is dried over sodium sulfate and concentrated by evaporation in vacuo. The crude, residual, 4- [2-[2-(p-ethoxybenzyl)-5-methyl-3-benzofuranyl]-ethyl]- morpholine is dissolved in ether and to the solution is added a slight excess of ethereal hydrochloric acid. The precipitated hydrochloride crystallizes upon triturating. After recrystallization from acetone/ether are obtained 1.9 g. of colorless crystals of the 4-[2-[2-(p-ethoxybenzyl)-5-methyl-3-benzofuranyl]-ethyl]-morpholine hydrochloride, m.p. 172l74. Yield 93 percent of theoretical value.

EXAMPLE 5 a. 2.3 g. of p-toluenesulfonic acid-2-[2-(p-ethoxybenzyl)-5- methyl-3-benzofuranyl]-ethyl ester [cp. example l(a)-(e)] are dissolved in 30 ml. of a saturated solution of dimethylamine in dimethylformamide and allowed to stand for 24 hours at room temperature. The reaction solution is then concentrated by evaporation in vacuo and the residue taken up with water and ether. The ethereal phase is washed with water, dried over sodium sulfate and concentrated by evaporation in vacuo. The crude N,N-dimethy1-2-(p-ethoxybenzyl)-5-methy1-3-benzofuran ethylamine which remains is dissolved in ether and a slight excess of ethereal hydrochloric acid is added. The precipitated hydrochloride is separated and recrystallized from acetone/ether, whereby 1.7 g. of N,N,5- trimethyl-2-(p-ethoxybenzyl)-3-benzofuran ethylamine hydrochloride, m.p. l56-l58, are obtained. Yield 91 percent of theoretical value.

b. In an analogous manner 2.3 g. of p-toluene sulfonic acid- 2-[Z-(p-ethoxybenzyl)-5-methyl-3-benzofuranyl]-ethy1 ester are reacted with 10 ml. of di-n-propylamine to give 1-[2[2-(pethoxybenzyl)-5-methyl-3-benzofuranyl]-ethyl]-di-npropylamine, the hydrochloride of which melts, after recrystallization from acetone/ether, at 107-l08 (yield 1.46 g., 64 percent of theory).

Similarly, 2.3 g. of p-toluene sulfonic acid-2-[2-(p-ethoxybenzyl)-5-methyl-3-benzofuranyl]-ethyl ester are reacted with 10 ml. of di-n-butylamine to give l[2-[2-(p-ethoxybenzyl )-5-methyl-3-benzofuranyl ]-ethyl l-di-n-butylamine, the hydrochloride of which, after recrystallization from acetone/ether, melts at l06l07 (yield 1.0 g., 45 percent of Theory).

EXAMPLE 6 a. 40.0 g. of [5-methoxy-2-(methoxycarbonyl)-phenoxy]- acetic acid methyl ester [m.p. 77-79 from ether/petroleum ether, cp. K. v. Auwers, Ann. 393, 352 (1912)] or 44.5 g. of

[5-methoxy-2-(ethoxycarbonyl)-phenoxy]-acetic acid ethyl ester (b.p. l57-l61l0.7 Torr) are added in portions at while stirring, to 3.64 g. of finely dispersed sodium in ml. of toluene. A thick slurry is formed with the dissolving of the sodium. As soon as all the sodium is dissolved (after ca. 3 hours), 34.0 g. of p-ethoxybenzyl bromide are added, while stirring, to the obtained sodium compound of the 5-methoxy- 3(2H)-oxo-3-benzofurancarboxylic acid methyl ester (or ethyl ester). The reaction mixture is subsequently refluxed while stirring, for 20 hours. The mixture is then cooled and water is added. The organic phase is separated, washed neutral, dried over sodium sulfate and concentrated by evaporation. Ca. 24.0 g. of substance, b.p. l l6l20/ 10 Torr, are distilled off from the residue under 10 Torr. The distillation residue of crude 2-(p-ethoxybenzyl)-5-methoxy-3(2H)- oxo-2-benzofurancarboxylic acid methyl ester (or -ethyl ester) is refluxed for 1 hour, to split off the carbalkoxy group, with 50 ml. of 10 percent methanolic potassium hydroxide solution. The methanol is then evaporated off in vacuo and the residue taken up with water and ether. The ether phase is washed neutral, dried over sodium sulfate and filtered through 100 g. of neutral aluminum oxide of Woelm activity stage 111. The extract, obtained by afterwashing with ether, is combined with the filtrate and concentrated by evaporation in vacuo. The residue yields, upon crystallization from ether/petroleum ether, 5.0 g. of 2-(p-ethoxybenzyl)-5-methoxy-3(2H benzofuranone as yellowish crystals, m.p. 92-94.

b. Analogously to example 1(0), 18 g. of 2-(p-ethoxybenzyl)-5-methoxy-3(2H)-benzofuranonewhich can also be produced analogously to example 1(a) and (b) starting with 5-methoxy-3(2H)-benzofuranone by way of Z-(p-ethoxybenzylidene )-5 -methoxy-3( 2H )-benzofuranone (m .p. l48-150 from ethanol)-are reacted with 43 g. of bromoacetic acid methyl ester to give the 2-( p-ethoxybenzyl)- 5-methoxy-3-benzofuranacetic acid methyl ester (oily).

c. Analogously to example l(d) is obtained from 3.74 g. of Z-(p-ethoxybenzyl)-5-methoxy-3-benzofuranacetic acid methyl ester, the 2-(p-ethoxybenzyl)-5-methoxy-3-benzofuran ethanol in the form of oil.

d. The alcohol, obtained according to (c), is converted, analogously to example l(e) into the p-toluenesulfonic acid-2- [2-(p-ethoxybenzyl)-S-methoxy-Ebenzofuranyl]-ethyl ester, m.p. l l3-l 14 (from ether/petroleum ether).

e. Analogously to example l(f), 2.4 g. of the p-toluene sulfonic acid ester, obtained according to (d), are reacted with 10 g. of pyrrolidine to give the 1-[2-[2-(p-ethoxybenzyl)-5- methoxy-3-benzofuranyl]-ethyl]-pyrrolidine and the latter is converted into its hydrochloride, m.p. l52l53 (from acetone/ether).

f. Analogously with 10 g. of diethylamine, the N,N-diethyl- 2-(p-ethoxybenzyl)-5-methoxy-3-benzofuran ethylamine and its hydrochloride are obtained m.p. 123-124. (Yield 50 percent of theory.)

EXAMPLE 7 a. Analogously to example 1(a), 45 g. of 5-chloro-3(2l-l)- benzofuranone [cp. K. Fries, A. l-lasselbach and L. Schroter, Ann. Chem. 405,346 (1914)] are condensed with 40.5 g. of pethoxybenz-aldehyde to give the 2-(p-ethoxybenzy1idene )-5- chloro-3(2H)-benzofuranone, m.p. 174-l 75.

b. 40 g. of the above condensation product are hydrogenated, analogously to example l(b) to give the 2-(pethoxybenzyl )-5-chloro-3( 2H )-benzofuranone, m.p. 777 8 (from ether).

c. Analogously to example KC), 19 g. of 2-(p-ethoxybenzyl)-5-chloro-3(2l-l)-benzofuranone are reacted with 43 g. of bromoacetic acid methyl ester to give the 2-(p-ethoxybenzyl)-5-chloro-3-benzofuran-acetic acid methyl ester (oily).

d. Analogously to example l(d), 3.8 g. of the reaction product of (c) are reduced to the crude Z-(p-ethoxybenzyD-S- chloro-3-benzofuran ethanol.

e. The crude alcohol, obtained in the case of (d) is con verted analogously to example le) into the p-toluenesulfonic acid-2-[2-(p-ethoxybenzyl)-5-chloro-3-benzofuranyl]-ethyl ester, m.p. l l-l03 (from ether/petroleum ether).

f. The reaction of 2.4 g. of the p-toluenesulfonic acid ester obtained according to (e) with 10 g. of pyrrolidine according to example l(f) yields the l-[2-[2-(p-ethoxybenzyl)-5-chloro- 3-benzofuranyl]-ethyl]-pyrrolidine, the hydrochloride of which, after recrystallization from acetone water, melts at l96-l97 (yield 1.7 g., 80 percent of theoretical value).

EXAMPLE 8 a. Analogously to example 2, 2.4 g. of p-toluenesulfonic acid-2-[2-(p-ethoxybenzyl)-5-chloro-3-benzofuranyl]-ethyl ester [cp. example 7(a)-(e)] are reacted with 0.6 ml. of piperidine to give the l-[2-[2-(p-ethoxybenzyl)-5-chloro-3- benzofuranyl1-ethyl]-piperidine, the hydrochloride of which melts after recrystallization from dioxane/water at 2l22l3 (yield 1.6 g., 74 percent oftheoretical value).

b. In an analogous manner 2.4 g. of p-toluenesulfonic acid- 2-[2-(-ethoxybenzyl)-5-chloro-3-benzofuranyl]-ethyl ester are reacted with dimethylamine to give 1.7 g. of N,N- dimethyl-2-(p-ethoxybenzyl)-5-chloro-3-benzofuranethylaminc-hydrochloride, m.p. l60-l6l (from acetone) (yield 85 percent of the theoretical value).

EXAMPLE 9 Analogously to example l(f), 2.4 g. of p-toluenesulfonic acid-2-[2-(p-ethoxybenzyl)-5-chloro-3-benzofuranyl]-ethyl ester [cp. example 7(a)(e)] are reacted with 10 ml. of morpholine to give the 4-[2-[2-(p-ethoxybenzyl)-5-chloro-3- benzofuranyl]-ethyl]-morpholine and its hydrochloride, m.p. 205-206(from water). Yield 1.9 g., 87 percent of theoretical value.

EXAMPLE l0 Analogously to example 3 is produced, by reaction of 2.4 g. of p-toluenesulfonic acid-2-[2-(p-ethoxybenzyl)-5-chl0ro-3- benzofuranyl1-ethyl ester [cp. example 7(a)(e)] with 10 ml. of diethylamine the 1-[2-[2-(p-ethoxybenzyl)-5-chloro-3- benzofuranyl]-ethyl]-diethylamine, the hydrochloride of which, after recrystallization from acetone/ether, melts at 129-l 30 (yield 1.8 g., 85 percent ofTheory).

In an analogous manner from 2,4-p-toluene sulfonic acid-2- [2-(p-ethoxybenzyl)-5-chloro-3-benzofuranyl]-ethyl ester, and 10 ml. of di-n-propylamine, is obtained the l-[2-[2-(pethoxybenzyl]--chlor0-3-benzofuranyll-ethyl]-di-npropylamine hydrochloride, m.p. 123124.

EXAMPLE 1 l a. The condensation of 36.2 g. of 3(2H )-benzofuranone with 40.5 g. of p-ethoxybenzaldehyde, analogously to example l(a), yields the Z-(p-ethoxybenzylidene)-3(2H)-benzofuranone, m.p. l35-l 36 (from ethanol).

b. Analogously to example l(b) is obtained, by hydrogenation of 36 g. of the above condensation product, the oily 2-(pethoxybenzyl)-3(2H )-benzofuranone.

c. From 16.2 g. of 2-(p-ethoxybenzyl)-3(2H)-benzofuranone and 43 g. of bromoacetic acid methyl ester is obtained, analogously to example l(c), the 2-(p-ethoxybenzyl)-3- benzofuranacetic acid methyl ester as an oil.

d. The reduction of 3.5 g. of the methyl ester, obtained according to (c), analogously to example l(d), yields the crude 2-(p-ethoxybenzyl)-3-benzofuran ethanol.

e. The crude alcohol, obtained according to (d), is converted, analogously to example l(e), into the p-toluenesulfonic acid-2-[2-(p-ethoxybenzyl)-3-benzofuranyl]-ethyl ester, m.p. 7374 (from ether/petroleum ether).

f. By reaction of 2.2 g. of the p-toluenesulfonic acid ester, obtained according to (e), with 30 ml. of a saturated solution of dimethylamine in dimethylformamide, analogously to example 5, is obtained the N,N-dimethyl-2-(p-ethoxybenzyl)-3- benzofuran ethylamine, and from that its hydrochloride, m.p. l7l-l73 (from acetone/ether). Yield 1.6 g., 89 percent of theoretic value.

EXAMPLE l2 Analogously to example 3, 2.2 g. of p-toluenesulfonic acid- 2-[2-(p-ethoxybenzyl)-3-benzofuranyl]-ethyl ester [cp. example la-(e) are reacted with 10 ml. of diethylamine to give the N,N-diethyl-2-(p-ethoxybenzyl)-3-benzofuran ethylamine. From the crude base are obtained 1.5 g. (77 per cent of theoretical value) of hydrochloride, m.p. l58-l6l (from acetone/ether).

EXAMPLE 1 3 Analogously to example l(f) 2.2 g. of p-toluenesulfonic acid-2-[2-(p-ethoxybenzyl)-3-benzofuranyl]-ethyl ester [cp. example 1 l(a)(e)] are reacted with 10 ml. of pyrrolidine to give the l-[2-[2-(p-ethoxybenzyl)-3-benzofuranyl]-ethyl]- pyrrolidine, the hydrochloride of which, after recrystallization from acetone/ether, melts at l93-l96. Yield 1.6 g., 83 percent of theoretical value.

EXAMPLE 14 2.2 g. of p-toluenesulfonic acid-2-[2-(p-ethoxy-benzyl)-3- benzofuranyll-ethyl ester [cp. example 1 l(a)(e)] are reacted with 10 m]. of piperidine, analogously to example l(f) to give the l-[2-[2-(p-ethoxybenzyl)-3-benzofuranyl]-ethyl]- piperidine. The hydrochloride of this base melts at l94-l 96 (from acetone/ether). Yield 1.7 g., 85 percent of theoretical value.

EXAMPLE 15 From 2.2 g. of p-toluenesulfonic acid-2-[2-(p-ethoxybenzyl)-3-benzofuranyl]-ethyl ester [cp. example 1 l(a)(e)] and 10 ml. of morpholine is obtained, analogously to example 4, the 4-[2-[2-(p-ethoxybenzyl)-3-benzofuranyl]-ethyl]- morpholine and from that is obtained the hydrochloride, m.p. l89-l92 (from acetone/ether). Yield 1.8 g., 90 percent of theoretical value.

EXAMPLE 16 a. 3.4 g. of 2-(p-ethoxybenzyl)-5-methyl-3-benzofuranacetic acid methyl ester [cp. example l(a)(e)] are heated with 16 g. of dimethylamine in a closed vessel for 24 hours to 1 10. The reaction mixture is then transferred to a flask and the dimethylamine evaporated off. The crystallization of the residue from acetone yields 1.9 g. of N,N,5-trimethyl-2-(pethoxybenzyl)-3-benzofuran acetamide as colorless crystals, m.p. 167-l68.

The following are produced analogously:

With 3.24 g. of 2-(p-ethoxybenzyl)-3-benzofuranacetic acid methyl ester [cp. example ll(a)-(c)] is produced the N,N- dimethyl-2-(p-ethoxybenzly)-3-benzofuran acetamide, m.p. 82-84 (from ether/petroleum ether); with 3.6 g. of 2-(pethoxybenzyl)-5-chloro-3-benzofuranacetic acid methyl ester [cp. example 7(a)-(c)] is produced the N,N-dimethyl-2-(pethoxybenzyl)5-chloro-3-benzofuran acetamide, m.p. l03105 (from ether/petroleum ether).

b. 0.5 g. of lithium aluminum hydride are suspended, while stirring, in 50 ml. of absoluteether and refluxed to boiling. A solution of 0.25 g. of N,N,5-trimethyl-2-(p-ethoxybenzyl)-3- benzofuran acetamide in 25 ml. of absolute ether is then slowly added dropwise and the mixture refluxed, while stirring, for a further 24 hours at boiling temperature. The reaction mixture is then carefully decomposed, while cooling with ice, with concentrated hydrochloric acid, an addition is made of 20 ml. of a semisaturated solution of potassium sodium tartrate (Seignettes salt) and then of concentrated aqueous ammonia solution until an alkaline reaction to litmus is obtained, the mixture shaken and the ether layer removed. The ether phase, washed with water and dried over sodium sulfate yields, after concentration by evaporation, ca. 0.212 g. of crude base. By dissolving the latter in acetone and adding ethereal hydrogen chloride solution, crude, oily hydrochloride is obtained, which crystallizes upon trituration. After recrystallization from acetone are obtained 0.215 g. of N,N, 5-trimethyl-2- (p-ethoxybenzyl)-3-benzofuran ethylamine hydrochloride, m.p. l56l58. Yield 80 percent of theoretical value.

The following are obtained analogously, using the same amounts of the corresponding dimethylamides: the N,N- dimethyl-2-(p-ethoxybenzyl)-3-benzofuran ethylamine hydrochloride, m.p. 171173 (from acetone) and the N,N- dimethyl2-(p-ethoxybenzyl)-5-chloro-3-benzofi.iran ethylamine hydrochloride, m.p. 160-l61 (from acetone).

EXAMPLE 17 a. 23.5 g. of 2(3l-l)-benzofuranone and 5 7 g. of bromoacetic acid methyl ester are dissolved together in 250 ml. of absolute benzene and slowly added dropwise to a mixture, being vigorously stirred and consisting of 30 g. of zinc wool, 0.1 g. of mercury(ll)-chloride and 100 ml. of boiling benzene. The zinc is practically fully dissolved after 3 hours and the reaction mixture is thereupon refluxed at boiling temperature for a further 4 hours. It is then cooled to room temperature and decomposed with 200 ml. of 2N sulfuric acid. The two-phase mixture is stirred for a further hour at room temperature, the benzene layer removed, washed until neutral, dried over sodium sulfate and concentrated by evaporation. Distillation of the residue under 10 Torr yields 4.0 g. of 3-benzofuranacetic acid methyl ester as colorless oil, B.P. l38145/l0 Torr. (Yield 12 percent of theoretical value).

The 5-methyl-3-benzofuranacetic acid methyl ester, b.p. 150] 1 1 Torr, is obtained analogously.

b. 3.9 g. of 3-benzofuranacetic acid methyl ester, dissolved in 10 ml. of absolute tetrahydrofuran, are added dropwise, while stirring, to a suspension of 1.5 g. of lithium aluminum hydride in 30 ml. of absolute tetrahydrofuran and refluxed for 3 hours.

The mixture is thereupon cooled with ice and decomposed with dilute hydrochloric acid. After the addition of 10 ml. of semisaturated solution of potassium sodium tartrate (Seignettes salt) and neutralization with concentrated aqueous ammonia solution, the tetrahydrofuran is evaporated ofl under vacuum and the obtained mixture, after being diluted with water, repeatedly extracted with ether. The ether extracts, washed until neutral and dried over sodium sulfate, are filtered through 20 g. of neutral aluminum oxide, Woelm activity stage 111, and eluted with ether. Filtrate and extract are combined and concentrated by evaporation, whereby 2.7 g. of crude 3-benzofuran ethanol are obtained (yield 89 percent).

c. The crude 3-benzofuran ethanol, obtained according to (b), is dissolved in 10 ml. of absolute pyridine and the solution cooled to l. 4.0 g. of p-toluenesulfochloride are added in portions in such a manner that the temperature does not exceed The mixture is allowed to stand for ca. 15 hours at 0, then poured into ice water and the precipitated oil triturated. Crystallization occurs after some time. Recrystallization from ethanol yields 4.0 g. of p-toluenesulfonic acid-2-( 3- benzofurany1)-ethy1 ester as crystals, m.p. 5849. (Yield 76 percent of theoretical value).

d. 3.3 g. of p-toluenesulfonic acid-2-(3-benzofuranyl)-ethy1 ester with 6.0 g. of liquid ammonia are heated in a closed vessel for 4 hours to 100. After evaporating off the ammonia, the reaction mixture is taken up with ether and 3 ml. of percent potassium carbonate solution. The ether phase is separated and dried over sodium sulfate and concentrated by evaporation 1.4 g. of 3-benzofuran ethylamine are obtained as an almost colorless oil (yield 93 percent of theoretical value).

e. To 1.0 g. of p-ethoxybenzoyl chloride is added at 0, a solution of 1.0 g. of 3-benzofuran ethylamine in 5 ml. of absolute pyrridine. After standing at room temperature for 4 hours, the reaction mixture is poured into water and extracted with ether. The ether phase is washed with dilute hydrochloric acid and then with water, dried over sodium sulfate and concentrated by evaporation. 1.5 g. of N-[2-(3-benzofuranyl)- ethyl]]-p-ethoxy-benzamide thereby precipitate as colorless crystals, m.p. 126. (Yield 70 percent of theoretical value).

f. 1.0 g. of phosphorus pentoxide and 2.0 g. of phosphorus oxychloride are added to 0.5 g. of N-[2-(3-benzofuranyl)- ethyl]-p-ethoxy-banzamide in 40 ml. of toluene. The mixture is refluxed for 4 hours to boiling while vigorously stirring. It is then cooled with ice, carefully decomposed by addition of a little water and the mixture transferred to a separating funnel by rinsing the reaction vessel with 40 ml. of chloroform. The organic phase yields, after being washed with water until neutral, dried with sodium sulfate and concentrated by evaporation in vacuo, 0.48 g. of residue. By crystallization of the latter from acetone, 0.45 g. of yellowish l-(p-ethoxyphenyl)-3,4-dihydrobenzofuro[ 2,3-c]-pyridine hydrochloride, m.p. -153, are obtained, yield 85, percent of theoretical value.

g. 0.2 g. of l-(p-ethoxyphenyl)-3,4-dihydrobenzofuro[2,3- clpyridine hydrochloride are heated in 5 ml. of diethylene glycol under nitrogen with 0.6 ml. of hydrazine hydrate and 0.5 g. of sodium hydroxide for one hour to 200. The reaction mixture is allowed to cool, poured into water and repeatedly extracted with ether. The combined ether solutions, washed with water and dried over sodium sulfate yield, after being concentrated by evaporation, 0.2 g. of crude 2-(p-ethoxybenzyl)-3-benzofuran ethylamine as a yellowish oil.

h. The crude amine, obtained according to (g), is refluxed with a mixture of 1 ml. of concentrated formic acid and 1 ml. of 37 percent formaldehyde solution for 24 hours. The reaction solution is then cooled, adjusted to pH 8-9 by addition of sodium carbonate solution and extracted with ether. The ether solution, washed until neutral with water and dried over sodium sulfate, is concentrated by evaporation and the residue chromatographed on a column prepared with 5.0 g. of neutral aluminum oxide, Woelm activity stage 111. The extract obtained with benzene is concentrated by evaporation, dissolved in ether and some acetone and to this solution is added a slight excess of ethereal hydrogen chloride solution. The precipitated N,N-dimethyl-2-(p-ethoxybenzyl)-3-benzofuran ethylamine hydrochloride crystallizes upon being triturated: m.p. 171l73 after recrystallization from acetone/ether.

i. 5-Methyl-3-benzofuran acetic acid is prepared after B. B. Dey and K. Radhabai, J. Ind. Chem. Soc. 11 635 (1934). 15.4 g. of 5-methyl-3-benzofuran acetic acid are added to a suspension of 9.0 g. of lithium aluminum hydride in 200 ml. of absolute diethyl ether and the resulting mixture is boiled under reflux for 4 hours with stirring. The reaction mixture is then cooled with ice and decomposed by the addition, dropwise, of 35 ml. of water and 7.5 ml. of 30 percent sodium hydroxide solution. The granular precipitate is removed by filtration from the ether solution and it is washed with ether. After the removal by distillation of the ether there remain 14.0 g. of 5- methyl-3-benzofuran ethanol as a colorless oil. Yield 97 percent of Theory.

Analogously to (c) is obtained by the reaction of the preceding alcohol (14 g.) with 14 g. of p-toulenesulfochloride in 60 m1. of pyrridine, 24 g. of p-toulenesulfonic acid-2-(5- methyl-3-benzofuran)-ethyl ester as a yellowish oil, (yield 91 percent of Theory), and from this, after reaction with 124 g. of liquid ammonia at 100 in a high-pressure vessel, analogously to (d), 9.7 g. of 5-methyl-3-benzofuran ethylamine as a colorless oil. Yield 76 percent of theory.

Analogously to (e) is obtained from 9.7 g. of the preceding amine and 12.0 g. of p-ethoxybenzoyl chloride 15.2 g. of N-[2- (5-methyl-3-benzofuranyl)-ethyl]-p-ethoxybenzamide, m.p. 1 12-1 13. Yield 85 percent of theory.

Analogously to (f) is obtained from 16.0 g. of the preceding amide, after treatment with 15.0 g. of phosphorus pentoxide and 13 ml. of phosphorus oxychloride in 300 m1. of toluene and crystallization from acetone, 16.5 g. of l-(p-ethoxyphenyl)-6-methy1-3,4-dihydro-benzofuro[2,3-c]-pyrridinehydrochloride, m.p. l70-171. Yield 98 percent of theory.

. 1.9 EXAMPLE 18 i. a. 27.0 g. of tin tetrachloride are slowly added dropwise, while stirring, to a solution of 25.5 g. of '2-(p-ethoxybenzyl)- benzofuran and 9.0 g. of acetyl chloride in 40 ml. of carbon disulfide. The reaction mixture is further stirred for 19 hours at room temperature, then decomposed, while cooling with ice, by the addition of water. The mixture extracted with chloroform. The chloroform solution is washed until neutral, dried over sodium sulfate and concentrated by evaporation in vacuo. 33 g. of a brown oil remain, which are chromatographed on 500 g. of neutral aluminum oxide, Woelm activity stage Ill, in the system benzene/petroleum ether 1 :1 v/v). The first three fractions (total volume 1.5 liters) yield, after concentration by evaporation from ether/petroleum ether, 13.0 g. of 2-(p-ethoxybenzyl)-3-acetylbenzofuran (2-(p-ethoxybenzyl)-3-benzofuranyl-methyl ketone), m.p. 71-72 (yield 42 percent of theoretical value). After recrystallization from petroleum ether, the ketone melts at 73-74. From the subsequent fractions (elution agent benzene/ether (9:1 v/v) are obtained, by crystallization from ether, 3.6 g. of Z-(p-hydroxbenzyl)-3-acetyl benzofuran, m.p. 148.

b. 5.0 g. of 2-(p-ethoxybenzyl)-3-acetyl-benzofuran are dissolved in 50 ml. of carbon tetrachloride and to this is firstly added, while stirring, 0.1 g. of dibenzoyl peroxide. While cooling with ice, 3.0 g. of bromine, dissolved in 50 ml. of carbon tetrachloride, are added dropwise within one hour. The reaction solution is then allowed to stand for a further hour at room temperature. After washing with water and sodium bicarbonate solution, drying over sodium sulfate and concentrating by evaporation, is obtained the 2-(p-ethosybenzyl)-3- bromoacetylbenzofuran as a brown oil, which is directly further used.

c. The crude bromo ketone of (b) is dissolved in 50 ml. of ether, 5 ml. of pyrrolidine are added and the solution is refluxed for one and a half hours. The reaction mixture is then washed neutral with water, dried with sodium sulfate and concentrated by evaporation. Theresidue is taken up in benzene to remove volatile, adhering pyrrolidine, and concentrated by evaporation in vacuo. The crude base remaining is dissolved in ether and to the solution is added a slight excess of ethereal hydrogen chloride solution. The precipitated 2-(p-ethoxybenzyl)-3-( l-pyrrolidinyl-acetyl)-benzofuran hydrochloride (2-(p-ethoxybenzyl)-3-benzofuranyll-pyrrolidinyl-methyl)- ketone hydrochloride) is crystallized from acetone/ether, whereby 3.4 g. m.p. l82-187 (with decomposition) are obtained (Yield 51 percent of theoretic value). d. 0.50 g. of 2-(pethoxybenzyl )-3-( l-pyrrolidinyl-acetyl)-benzofuran hydrochloride are suspended in a little water. To this is added a slight excess of ammonia and the liberated base extracted with ether. After drying over magnesium sulfate, the ether solution of the base is concentrated to a volume of 3 ml. and at a mixture of ml. of boron trifluoride etherate and 5 ml. of tetrahydrofuran is added dropwise. A white precipitate thereby forms which immediately goes into solution again. After allowing the solution to stand at room temperature for 30 minutes, 2 ml. of 1.8-molar diborane solution in tetrahydrofuran are added (slight evolution of gas) and ether is distilled off until the temperature of the reaction mixture is 55. The reaction mixture is then refluxed for half an hour, a further addition made of 1 ml. of diborane solution with refluxing proceeding for a further half an hour. After concentrating the reaction mixture by evaporation in vacuo, the residue is decomposed with methanol and again concentrated by evaporation. Water and ice are added to the residue and the mixture made alkaline with ammonia. The precipitated base is extracted with ether, the ether solution washed with water, dried over sodium sulfate filtered through 5 g. of neutral aluminum oxide, Woelm activity stage ill, and the aluminum oxide subsequently washed with ether. Filtrate and extract are combined and a small excess of ethereal hydrogen chloride solution is then added. The precipitated crude l-[2- [2-( p-ethoxybenzyl )-3-benzofuranyl J-ethyl ]-pyrrolidine hydrochloride is separated and recrystallized from acetone/ether, whereby 0.40 g. of colorless needles, mp. 193 -196", are obtained. (Yield 83 percent of theoretical value.)

ii. 122 g. of Salicylaldehyde are added to a solution of 62 g. of potassium hydroxide in 1,800 ml. of ethanol. 250 g. of pethoxyphenacy1-bromide are added to the solution and it is stirred for 5 hours at boiling point under reflux. The thus formed potassium bromide is then filtered ofi and the filtrate evaporated under vacuum. During the evaporation the product crystallizes out. After recrystallization from ethanol 170 g. of Z-p-ethoxybenzoyl-benzofixran is obtained, m.p. 98-101 (yield 60 percent of theory). 100 g. of 2-p-ethoxybenzoyl-benzofuran are dissolved in 250 ml. of diethylene glycol, mixed with 92 g. of hydrazine hydrate and the mixture heated at boiling point for 15 minutes. The mixture is left to cool and afier the addition of 83 g. of potassium hydroxide it is heated in a distillation apparatus for 3% hours at 200. After cooling the reaction mixture is poured into ice and acidified with 1,200 mi. of Z-hydrochloric acid. The product is extracted with benzene, the extract washed with water, dried over sodium sulfate, evaporated in vacuo at 60 and the residual oil is distilled in vacuo. 71 g. of 2-p-ethoxybenzylbenzofuran b.p. 214-216 at 13 Torr are obtained. (Yield 75 percent of theory.)

Similarly are obtained from 10 g. S-Methylsalicyl aldehyde,

24 g. S-Chloro-salicyl aldehyde and 20 g. S-Methoxysalicyl aldehyde, after crystallization from ethanol,

12. g. 2-( p-ethoxybenzoyl )-5-methylbenzofuran, m .p. l00l01, (yield 59 percent of theory) 24.5 g. 2-( p-ethoxybenzoyl )-5-chlorobenzofuran, m .p.

l29l 3 1 (yield 53 percent ofTheory) 31.0 g. 2-(p-ethoxybenzoyl)-5-methoxybenzofuran, m.p. l l3l l5 (yield 79 percent of Theory), respectively,

and from these, after reduction with hydrazine hydrate, vacuum distillation in a particle tube and crystallization from methanol 8.8 g. 2-(p-ethoxybenzyl)-5-methylbenzofuran, m.p. 3839 (yield 77 percent of Theory) 13 g. 2-(p-ethoxybenzyl)-5-chlorobenzofuran, m.p. 48-49 (yield 5 6 percent of Theory) 16 g. 2-(p-ethexybenzyl)-5-methoxy-benzofuran, 52-53 (yield 54 percent of theory), respectively,

e. To a solution of 8.5 g. of 2-(p-ethoxybenzyl)-5-methylbenzofuran and 2.4 g. of acetyl chloride in 50 ml. of carbon disulfide, 3.3 ml. of titanium tetrachloride are added dropwise slowly and with stirring. The reaction mixture is stirred for a further 19 hours at room temperature, water is then added with ice cooling, and the mixture is extracted with chloroform. The chloroform solution is washed neutral, dried over sodium sulfate and evaporated in vacuo. The residual oil precipitates directly from methanol as crystals. After recrystallization of these crystals from ether, 8.5 g. of 2-(p-ethoxybenzyl)-5- methyl-3-acetylbenzofuran, m.p. 73-74 is obtained (yield 76 percent of theory).

In an analogous manner is obtained from 13 g. of 2-(pethoxybenzyl)5-chlorobenzofuran, after reaction with 3.4 g. of acetyl chloride and 4.75 ml. of titanium tetrachloride and crystallization of the isolated crude product from methanol, 8.0 g. of 2-(p-ethoxybenzyl)-5-chloro-3-acetyl-benzofuran m.p. 9395, (yield 53 percent of theory).

Analogously to (b) is obtained from 2.83 g. of 2-(p-ethoxybenzyl)-5-methyl-3-acetylbenzofuran and 0.55 ml. of bromine, 2-(p-ethoxybenzyl)-5-methyl-3-bromoacetylbenzofuran, which gives after recrystallization from ether, 2.6 g. of crystals, m.p. 95 96 (yield 73 percent of theory).

Analogously to (b) is obtained from 3.28 g. of Z-(p-ethoxybenzyl)-5-chloro-S-acetyl-benzofuran and 0.57 ml. of bromine, 2-(p-ethoxybenzyl)-5-chloro-3-bromo-acetylbenzofuran, which gives after crystallization from ether, 3.7 g. of crystals, m.p. 107-109 (yield 91 percent of theory).

Analogously to (c) is obtained from 1 g. of 2-(p-ethoxybenzyl)--methyl-3-br0moacetyl benzofuran and 1.0 ml. of pyrrolidine after isolation of the crude base, conversion of the same into its hydrochloride and crystallization from acetone/ether, 0.50 g. of 2-(p-ethoxybenzyl)-5-methyl-3-(1- pyrrolidinyl-acetyl)-benzofuran-hydrochloride, m.p. l62-l6 5 (decomposition). Yield 47 percent of theory. Also, with 1.0 ml. of piperidine, after crystallization from water, 0.60 g. of 2- (p-ethoxybenzyl)-5-methyl-3-( 1-piperidinyl-acetyl)-benzofuran-hydrochloride, m.p. l72174 (with decomposition). Yield 67 percent of theory.

Analogously to (c) is obtained from 2.7 g. of 2-(p-ethoxybenzyl)-5-chloro-3-bromo-acetyl-benzofuran and 3 ml. of pyrrolidine, after crystallization from acetone, 1.6 g. of 2-(pethoxybenzyl)-5-chloro-3-(pyrrolidinyl-acetyl)-benzofuranhydrochloride, m.p. l86190 (with decomposition). Yield 56 percent of theory. Also, with 3 ml. of diethylamine, after crystallization from acetone/ether, 1.8 g. of 2-(p-ethoxybenzyl)-5-chloro-3-(N-diethylamino-acetyl)-benzofuranhydrochloride m.p. l50-l52 (decomposition). Yield 63 percent of theory.

Analogously to (d) is obtained from 0.5 g. of 2-(p-ethoxybenzyl )-5-methyl-3-( 1-pyrrolidinyl-acetyl )-benzofuranhydrochloride, after liberation of the base and treating the same with 5 ml. of borontrifluoride etherate and 3 ml. of 1.8 molar diborane solution in tetrahydrofuran after final processing and crystallization from acetone 0.35 g. of 1-[2-[2- (p-ethosy-benzyl)-5-methyl-3-benzofuranyl]-ethyll-pyrralidine-hydrochloride, m.p. 167169 (yield 72 percent of theory). Also is obtained from 0.5 g. of 2-(p-ethoxybenzyl)-5- methyl-3-( 1 -piperidinyl-acetyl )-benzofuran-hydrochloride, after crystallization from methanol/acetone 0.26 g. of l-[2[2- (p-ethoxy-benzyl)-5-methyl-3-benzofuranyl]ethyl]- piperidine-hydrochloride, m.p. 192-l93 (yield 54 percent of theory).

Analogously to (d) is obtained from 1.0 g. of 2-(p-ethoxybenzyl )-5-chloro-3-( l-pyrrolidinyl-acetyl )-benzofuranhydrochloride, after liberation of the base and treatment of the same with ml. of borontrifluoride etherate and 6 ml. of 1.8 molar diborane solution in tetrahydrofuran after final processing and crystallization from acetone, 0.5 g. of l-[2-[2- (p-ethoxybenzyl-5-chloro-3-benzofuranyl]-ethyl]-pyrrolidinehydrochloride, m.p. 196-l97 (yield 51 percent of theory). Also is obtained from 1.0 g. of Z-(p-ethosybenzyl) 5-chloro-3- (N-diethylamino-acetyl)-benzofuran-hydrochloride, after crystallization from acetone/ether, 0.6 g. of N,N-diethyl-2-(pethoxybenzyl)-5-chloro-3-ben2ofuran-ethylamine hydrochloride, m.p. l29-130 (yield 62 percent of theory).

EXAMPLE 19 a. 26.0 g. of Z-(p-ethoxybenzyl)-5-chloro-3(2l'l)-benzofuranone [cp. example 7(a) and (b) and 67.0 g. of bromoacetic acid ethyl ester are dissolved together in 430 ml. of absolute benzene and the solution is slowly added dropwise to a mixture of 31.5 g. of zinc wool, 0.1 g. of mercury (ll)- chloride and 150 ml. of boiling benzene, whereby the mixture is vigorously stirred. Practically all the zinc is dissolved after 3 hours. The reaction mixture is then refluxed, while stirring, for a further 4 hours at boiling temperature. it is then cooled to 0 and stirred for half an hour with 300 ml. of 2N sulfuric acid. The benzene layer is then removed, washed neutral, dried over sodium sulfate and filtered through a chromatography column charged with 500 g. of neutral aluminum oxide, Woelm activity stage 111. After eluting with benzene and con centrating the filtrate and extract by evaporation, 19.7 g. of oily 2-(p-ethoxybenzyl)-3-hydroxy-5-chloro 2,3-dihydro3- benzofuranacetic acid ethyl ester are obtained (61 percent of theoretical value). The ester is obtained, from ether/petroleum ether, as colorless crystals, m.p. 83.5-84. Yield ca. 54 percent of theory.

b. 19.5 g. of Z-(p-ethoxybenzyl)-3-hydroxy-5-chloro-2,3- dihydro-3-benzofuranacetic acid ethyl ester are dissolved in ml. of tetrahydrofuran and added dropwise, while stirring, to a suspension of 8.9 g. of lithium aluminum hydride in 100 ml. of tetrahydrofuran and refluxed for 3 hours. The mixture is thereupon cooled to 5 and decomposed by the addition, dropwise, of ethyl acetate. The mixture is then adjusted to pH 3-4 with 2N hydrochloric acid and concentrated at 30 in vacuo. To the concentrate is added a solution of 20 g. of potassium sodium tartrate (Seignettes salt) and the mixture is adjusted to pH 8 with concentrated ammonia. After extraction with ether, washing of the ether solution, drying over sodium sulfate and concentration by evaporation, are obtained 18.0 g. of oily crude product. This is applied to a chromatography column charged with 600 g. of neutral aluminum oxide, Woelm activity stage ill, and eluted with benzene. The evaporation residue of the extract is crystallized from ether/petroleum ether, whereby 12.2 g. of 2-(p-ethoxybenzyl)-3-hydroxy-5-chloro-2,3-dihydro-3-benzofuran ethanol are obtained as colorless crystals, m.p. 96-98.

c. 12.2 g. of the alcohol, obtained according to (b), are dissolved in l 15 ml. of absolute pyridine and the solution cooled to l0. 22.8 g. of p-toluene sulfochloride are added in portions in such a manner that the temperature does not exceed -*5. The mixture is allowed to stand for ca. 15 hours at 0 and is then poured into ice water. The precipitated oil is taken up in chloroform and the solution cleared of adhering pyridine by shaking with 0.5N hydrochloric acid. The chloroform solution is then washed neutral, dried over sodium sulfate and concentrated by evaporation. By crystallization of the residue from ether/petroleum ether are obtained 9.0 g. of p-toluenesulfonic acid-2-[2b-(p-ethoxybenzyl)-3-hydroxy-5-chloro-2,3-dihydro- 3-benzofuranyl1-ethyl ester as colorless crystals, m.p. 1 12-l 1 3, yield 54 percent of theoretical value.

d. 2.5 g. of the p-toluenesulfonic acid ester of (c) are refluxed with 30 ml. of morpholine for 5 hours with a bath temperature of Zreaction mixture is then completely concentrated by evaporation in vacuo, to the residue are added 20 ml. of benzene and the reaction mixture is again concentrated by evaporation. This is repeated until all the volatile amine has been expelled. The residue is taken up with water and ether. The ethereal phase is washed with water and then extracted twice using 5 ml. of 1N sulfuric acid each time. The acid extracts are adjusted to pH 9 with concentrated ammonia and the hereby precipitated (oily) base extracted with ether. The ether solution, washed and then dried over sodium sulfate, is concentrated by evaporation, the crude base remaining is dissolved in acetone and to the solution is added a small excess of ethereal hydrogen chloride solution. The precipitated hydrochloride crystallizes upon triturating. After recrystallization from acetone are obtained 1.73 g. of 4-[2-[0- (p-ethoxybenzyl)-3-hydroxy-5-chloro-2,3-dihydro-3-benzofuranyl]-ethyl]-morpholine hydrochloride, m.p. l94-l96.

e. 1.65 g of 4-[2-[Z-(pethoxybenzyl)-3-hydroxy-5-chloro- 2,3-dihydro-3-benzofuranyl]-ethyl]-morpholine hydrochloride are dissolved in 20 ml. of absolute dioxane, to the solution are added 0.17 g. of p-toluenesulfonic acid and the mixture is refluxed for one hour. The reaction mixture is then concentrated in vacuo at 20, made alkaline with 2N sodium carbonate solution and repeatedly extracted with ether. The combined ether extracts are washed with water, dried over sodium sulfate and concentrated by evaporation. The residue is dissolved in ether and a small excess of ethereal hydrogen chloride solution is added. The precipitated 4-[2-[2- (p-ethoxybenzyl)-5-chloro-3-benzofuranyl]-ethyl]- morpholine hydrochloride is crystallized from water, m.p. 205-206. Yield 1.46 g., 91.5 percent of theoretical value.

f. Analogously to (d) is obtained the l[2-[2-(p-ethoxybenzyl)-3hydroxy-5-chloro-2,3-dihydro-3-benzofuranyl]- ethyl]-pyrrolidine hydrochloride, m.p. 196197 (from acetone/ether).

g. Analogously to example 10 is obtained, from the ptoluene sulfonic acid ester obtained in (c) by reaction with diethylamine, the l-[2-[2-(p-ethoxybenzyl)-3-hydroxy-5- chloro-2,3-dihydro-3-benzofuranyl]-ethyl]-diethylamine hydrochloride, m.p. l72-l73 (from acetone/ether).

23 EXAMPLE 20 a. 2.5 g. of p-toluenesulfonic acid-2-[2-(p-ethoxybenzyl)-3- hydroxy-S-chloro-Z,3-dihydro-3-benzofuranyl]-ethyl ester [cp. example l9(a)-(c)] are refluxed with 30 ml. of piperidine for 5 hours. Preparation and production of the hydrochloride are carried out analogously to example 19(c). 1.6 g. of l-[2- [Z-(p-ethoxybenzyl)-3-hydroxy-5-chloro2,3-dihydro-3- benzofuranyl]-ethyl]-piperidine hydrochloride, m.p. l0620 7 are obtained (from acetone/water).

b. 1.60 g. of the hydrochloride, obtained according to (a), are dissolved in 30 ml. of dioxane. 7 ml. of saturated ethereal hydrogen chloride solution are 'added to the solution and the latter refluxed for one hour. The reaction solution is then concentrated in vacuo to a volume of ca. 8 ml. With the addition of water, 1.5 g. of l-[2-[2-(p-ethoxybenzyl)-5-chloro-3- benzofuranyl]-ethyl]-piperidine hydrochloride, m.p. 212-2l 3, crystallize.

c. In an analogous manner is obtained from 2.2. g. of l-[2- [2-(p-ethoxybenzyl)-3-hydroxy-5-chloro-2,3-dihydro-3- benzofuranyl]-ethyl]-diethylamine-hydrochloride after crystallization from acetone/ether 2.0 g. of l-[2-[2-(p-ethoxybenzyl)-5-chloro-3-benzofuranyl]ethyl]-cliethylaminehydrochloride, m.p. l29-l30, (Yield 95 percent of theory) and from 2.0 g. of l-[2-[2-(p-ethoxybenzyl)-3-hydroxy-5- chloro-2,3-dihydro-3-benzofuranyl]-ethyl]-pyrrolidinehydrochloride, after crystallization from acetone/ether 1.8 g. of l-[ 2-[ 2-( p-ethoxybenzyl )-5-chloro-3-benzofuranyl l-ethyl pyrrolidine-hydrochloride, m.p. l96l97. Yield 94 percent of theory.

EXAMPLE 21 a. 3.4 g. of Z-(p-ethoxybenzyl)-5-methyl-3-benzofuranacetic acid methyl ester are refluxed with 12 ml. of 1N potassium hydroxide solution and 20 ml. of ethanol for 2 hours. The ethanol is evaporated off, the mixture acidified with 2N sulfuric acid, the ether solution, washed and then dried over sodium sulfate, is extracted with ether and concentrated by evaporation, whereby the corresponding crude acid is obtained. By crystallization from ether/petroleum ether are obtained 2.0 g. of pure 2-(p-ethoxybenzyl)-5-methyl-3- benzofuran acetic acid as colorless needles, m.p. l74-l75. (Yield 60 percent of theoretical value).

b. in an analogous manner 3.0 g. of 2-(p-isopropoxybenzyl)- 5-methyl-3benzofuran acetic acid ethyl ester are hydrolyzed with 12 ml. of l-n potassium hydroxide solution. After crystallization from ether/petrol ether 1.57 g. of 2-(pisopropoxybenzyl)-5-methyl-3-benzofuran acetic acid are obtained, m.p. l22-l 25, (yield 64 percent of theory).

3.2 g. of 2-(p-ethoxybenzyl)-5-chloro-3-benzofuran acetic acid methyl ester are hydrolyzed with 12 ml. of l-potassium hydroxide solution. After crystallization from ether/petroleum ether are obtained 2.0 g. of 2-(p-ethoxybenzyl)-5-chloro-3- benzofuran acetic acid: m.p. l56-l57, (yield 65 percent of theory).

3.0 g. of 2-(p-ethoxybenzyl)-5-methoxy-3-benzofuran acetic acid methyl ester are hydrolyzed with 12 ml. of l-n potassium hydroxide solution. After crystallization from ether/petroleum ether are obtained 1.8 g. of 2-(pethoxybenzyl)-5-methoxy-3-benzofuran acetic acid, m.p. 146-l48 (yield 65 percent of theory).

EXAMPLE 22 i. a. 18.0 g. of 5-methyl-3(2H)-benzofuran and 20.0 g. of pisopropoxybenzaldehyde are reacted in 20 ml. of ethanol and 1 ml. of concentrated hydrochloric acid analogously to example la. After crystallization from ethanol are obtained 21.0 g. of 2-(p-isopropoxybenzylidene)-5-methyl-3(2H)-benzofuran, m.p. 132-l 33. Yield 58 percent of theoretical value.

b. 20.0 g. of the benzylidene compound are hydrogenated, analogously to example 1(b), in 400 ml. of dioxane in the presence of 4 g. of the therein stated catalyst. Crystallization of the crude product from ether/petroleum ether yields 12.0 g.

of 2-( p-isopropoxybenzyl )-5 -methyl-3( 2H )-benzofuranone, m.p. 8082. Yield 60 percent of theoretical value.

c. 10.0 g. of 2-(p-isopropoxybenzyl)-5-methyl-3(2H)- benzofuran, 26.2 g. of bromoacetic acid ethyl ester and l 1.4 g. of zinc wool are reacted analogously to example 10. After purification on g. of neutral aluminum oxide, Woelm activity stage 111, 10.0 g. of 2-(p-isopropoxybenzyl)-5-methyl-3- benzofuran acetic acid ethyl ester are obtained as an oily product. Yield percent of theoretical value.

d. 12.0 g. of 2-(p-isopropoxybenzyl)-5-methyl-3-benzofuran acetic acid ethyl ester are reduced, analogously to example 1d, with 5.6 g. of lithium aluminum hydride. 10.0 g. of crude product are obtained and from that, after purification on 200 g. of neutral aluminum oxide, Woelm activity stage III, are obtained 7.0 g. of 2-(p-isopropoxybenzyl)-5-methyl-3- benzofuran ethanol as colorless oil. Yield 66 percent of theoretical value.

e. 3.5 g. of Z-(p-isopropoxybenzyl)-5-methyl-3-benzofuran ethanol are reacted, analogously to example 1e with 6.7 g. of p-toluene sulfochloride. After crystallization from ether/petroleum ether are obtained 4.2 g. of p-toluenesulfonic acid-2-[Zb-(p-isopropoxybenzyl)-5-methyl-3-benzofuranyl]- ethyl ester as colorless crystals, m.p. l l0-l 1 1.

f. 4.2 g. of p-toluenesulfonic acid-2-[2-(p-isopropoxybenzyl)-5-methyl-3-benzofuranyl]-ethyl ester and 20 ml. of pyrrolidine are reacted, analogously to example 1 f. After crystallization from acetone/ether are obtained 2.9 g. of 1-[2- [2-( p-isopropoxybenzyl)-5 -methyl-3-benzofuranyl]-ethyl pyrrolidine hydrochloride, m.p. l9l-l92. Yield 80 percent of theoretical value.

ii. In an analogous manner 2.0 g. of p-toluene sulfonic acid- 2-[2-(p-isopropoxybenzyl)-5-methyl-3-benzofuranyl]-ethyl ester are reacted with 0.6 ml. of piperidine. The crude base obtained produces 1.88 g. of its crystalline hydrogen sulfate by the addition of 2-sulfuric acid. After recrystallization from acetone, 1.68 g. of l-[2-[2-(p-isopropoxybenzyl)-5-methyl-3- benzofuranyll-ethyll-piperidine hydrogen sulfate are obtained, m.p. l7 l-l72, (yield 82 percent of theory). Analogously, 2.0 g. of p-toluene sulfonic acid-2-[2-(pisopropoxybenzyl)-5-methyl-3-benzofuranyl]-ethyl ester are reacted with 10 ml. of morpholine to give 4-[2-[2-(pisopropoxybenzyl)5-methyl-3-benzofuranyl ]-ethyl morpholine, the hydrochloride of which melts, after recrystallization from acetone, at l99-200, yield 1.44 g., 80 percent of theory. in a similar manner is obtained from 2.0 g. of the ptoluene sulfonic acid ester and 10 ml. di-n-propylamine the N,N-dipropyl-2-(p-isopropoxybenzy)- 5-methyl-3-benzofuran ethylamine, the hydrochloride of which melts after recrystallization from acetone/ether at l63-l64, yield 1.48 g., 78 percent of theory.

EXAMPLE 23 a. 14.8 g. of 5-Methyl-3(2H)-benzofuranone and 13.6 g. of anisaldehyde are reacted in 5 ml. of ethanol and 1 ml. of concentrated sulfuric acid, analogously to example la. After crystallization from ethanol, 12.5 g. of Z-p-(methoxybenzylidene)-5-methyl-3(2H)-benzofuranone are obtained, m.p. 152, yield 47 percent of theory.

b. 12.5 g. of the benzylidene compound are hydrogenated analogously to example 1b in 250 ml. of dioxane in the presence of 2.5 g. of the therein mentioned catalyst. The crystallization of the crude product from ether/petroleum ether gives 9.5 g. of Z-(p-methoxybenzyl)-5-methyl-3(2l-l)- benzofuranone, m.p. 5659, yield 76 percent of theory.

c. 9.0 g. of 2-(p-Methoxybcrlzyl)-5-methyl-3(2l-l)-benzofuranone, 26.2 g. of bromoacetic acid ethyl ester and 1 1.4 g. of zinc wool are reacted together analogously to example 10. After purifying on 70 g. of neutral aluminum oxide, Woelm activity stage III, 10.0 g. of 2-(p-methoxybenzyl)-5-methyl-3- benzofuran acetic acid ethyl ester are obtained as oily product, (yield 89 percent of theory). IR in substance: 1,740 cm.CO.

d. 10.0 g. of 2-(p-Methoxybenzyl)-5-methyl-3-benzofuran acetic acid ethyl ester are reduced, analogously to example 1d,

with 5.1 g. of lithium aluminumhydride. 9.0 g. of crude product are obtained, and after purifying on 160 g. of neutral aluminum oxide, Woelm activity stage III, 7.0 g. of 2-(pmethoxybenzyl)--methyl-3-benzofuran-ethano1 are obtained as a colorless oil. (Yield 83 percent of theory).

e. 7.0 g. of 2-(pMethoxybenzyl)-5-methyl-3-benzofuran ethanol are reacted analogously to example 1e with 15.3 g. of p-toluene sulfochloride. 6.0 g. of crude oily p-toluene sulfonic acid-2-[Z-(p-methoxy-benzyl)-5-methyl-3-benzofuranyl]- ethyl ester are obtained, yield 55 percent of theory.

f. 6.0 g. of p-toulenesulfonic acid-2-[2-(p-methoxy-benzyl)- 5-methyl-3-benzofuranyl]-ethy1 ester and 30 ml. of pyrrolidine are reacted together, analogously to example 1 f. After crystallization from acetone, 3.0 g. of 1-[2-[2-(p-methoxybenzyl)-5-methy1-3-benzofuranyl]-ethyll-pyrrolidinehydrochloride are obtained, m.p. l83l84, yield 60 percent of theory.

EXAMPLE 24 a. 5.0 g. of 5-Methoxy-3(2H)-benzofuranone[cp. K. von Auwers and P. Pohl, Ann. 405 281 (1914)] are reacted with 6.0 g. of p-isopropoxy benzaldehyde in 5 ml. of ethanol and 0.5 ml. of concentrated hydrochloric acid. The separated crude product is recrystallized from ethanol. 6.6 g. of 2-(p- Isopropoxybenzylidene)-5-methoxy-3(2H)-benzofuranone are obtained as yellow needles, m.p. l03l04, yield 69 percent of theory.

b. 6.5 g. of 2-(p-isopropoxy-benzylidene)-5-methoxy-3 (2l-l)-benzofuranone are hydrogenated in 130 ml. of dioxane over 0.5 g. of catalyst (Spercent paladium on barium carbonate). 6.4 g. of crude 2-(p-isopropoxybenzyl)-5-methoxy-3 (2I-I)benzofuranone are obtained as an oil, yield 98 percent of theory. IR in Cl-I,Cl,=l710cmCO.

c. 4.5 g. of 2-(p-Isopropoxybenzyl)-5-methoxy-3(2l-I)- benzofuranone are reacted with 11.2 g. of bromoacetic acid ethyl ester and 5.0 g. of zinc wool in 100 ml. of benzene. 4.8 g. of oily 2-(p-isopropoxy-benzyl)-5-methoxy-3-benzofura.n acetic acid ethyl ester are obtained, yield 87 percent of theory. IR in substance=1740 cm CO.

d. 4.8 of 2-(p-Iospropoxybenzyl)-5-methoxy-3-benzofuran acetic acid ethyl ester are reduced, analogously to example 1d, with 2.2 g. of lithium aluminum hydride. 4.5 g. of crude product are obtained and from this, after purifying on 50 g. of neutral aluminum oxide, Woelm activity stage III, 4.0 g. of 2- (p-isopropoxy-benzyl)-5-methoxy-3-benzofuran ethanol are obtained as colorless oil. Yield 94 percent of theory. [R in CH,Cl 1r/a3610 cm"Ol-1.

e. 4.0 g. of 2-(p-isopropoxy-benzyl)-5-methoxy-3-benzofuran ethanol are reacted, analogously to example 1e, with 7.3 g. of p-toluene sulfochloride. 3.9 g. of crude oily p-toluene sulfonic acid-2-[2-(p-isopropoxy-benzyl)-5-methoxy-3-benzofuranyl]-ethyl ester are obtained, yield 67 percent of theory. IR in CH,Cl 1360, 1 180 cmSO.

f. 1.9 g. of p-toluene sulfonic acid-2-[2-(p-isopropoxybenzyl)-5-methoxy-3-benzofuranyll-ethyl ester are reacted with ml. of morpholine, analogously to example 4. After crystallization from acetone/ether 1.0 g. of 4-[2-[2-(pisopropoxybenzyl)-5-methoxy-3-benzofuranyl]-ethyl]- morpholine hydrochloride are obtained, m.p. 125l27. Yield 55 percent of theory.

EXAMPLE 25 a. 63 g. of 2-chloro-2'-hydroxy-4',5-dimethyl acetophenone [cp. S.S. Tiwari and Brajendra Nath Tripathi, J.

b. 45 g. of 5,6-dimethyl-3(2H)-benzofuranone and 30 g. of p-ethoxy-benzaldehyde are reacted in 55 ml. of ethanol and 3 ml. of concentrated hydrochloric acid, analogously to example 1a. After crystallization from ethanol, 50 g. of Z-(p-ethoxybenzylidene)-5,6-dimethyl-3(2H)-beazofuranone are ob tained, m.p. l38-139. Yield 61 percent of theory.

c. 44.5 g. of 2-(p-ethoxybenzylidene-S,6-dimethyl-3(2H)- benzofuranone are hydrogenated, analogously to example lb, in 900 ml. of dioxane and in the presence of 7 g. of the therein mentioned catalyst. The crystallization of the raw product from ether/petroleum ether produces 30.0 g. of 2-(p-ethoxybenzyl)-5,6-dimethyl-3(2H)-benzofuranone, m.p. 83-84, yield 67 percent of theory.

d. 11.0 g. of 2-(p ethoxybenzyl)-5,6-dimethyl-3(2H)- benzofuranone are reacted with 28.8 g. of bromoacetic acid ethyl ester and 13.7 g. of zinc wool. After purifying on 100 g. of neutral aluminum oxide, Woelm activity stage III, 10 g. of oily 2-(p-ethoxybenzyl)-5,6-dimethyl-3-benzofuran-acetic acid ethyl ester are obtained, yield 74 percent of theory. After recrystallization from ether/petroleum ether crystals are obtained, m.p. 78-79.

e. 10.0 g. of 2-(p-ethoxybenzyl)-5,6-dimethyl-3-benzofuran acetic acid ethyl ester are reduced analogously to example 1d with 3.4 g. of lithium aluminum hydride. 6.5 g. of crude product are obtained and after purifying on 50 g. of neutral aluminum oxide, Woelm activity stage III, and crystallization of the purified product from ether/petroleum ether, 5.3 g. of 2-(p-ethoxybenzyl)-5,6-dimethyl-3-benzofuran ethanol are obtained, m.p. 83-85. Yield 60 percent of theory.

f. 1.8 g. of 2-(p-ethoxybenzyl)-5,6-dimethyl-3-benzofuranethanol are reacted, analogously to example 1e, with 3.5 g. of p-toluene sulfochloride. After crystallization of the crude product from ether, 2.1 g. of p-toluenesulfonic acid-2-[2-(pethoxy-benzyl)-5,6-dimethyl-3-benzofuranyl]-ethyl ester are obtained, m.p. 142-l43. Yield 79 percent of theory.

g. 2.1 g. of p-toluenesulfonic acid-2-[2-(p-ethoxy-benzyl)- 5,6-dimethyl-3-benzofuranyl]-ethyl ester and 11 ml. of pyrrolidine are reacted analogously to example I f. After crystallization from acetone/ether 1.8 g. of l-[2-[2-(p-ethoxybenzyl)-5,6-dimethyl-3-benzofuranyl]-ethyl]-pyrro1idinehydrogen sulfate are obtained, m.p. 103-l04. Yield 86 percent of theory.

EXAMPLE 26 a. 7.0 g. of [4-nitro-2-(ethoxycarbonyl)-phenoxy]-acetic acid ethyl ester, [cf. W. A. Jacobs and M. Heidelberger, J.A.C.S. 39 2188 19l7)]m.p. 7576], are added in portions to 1.12 g. of 50 percent sodium hydride dispersion in 50 ml. of benzene with stirring at Upon the dissolving of the sodium hydride, a thicker slurry if formed. After the end of this reaction, 25.6 ml. of a 37 percent solution of p-ethoxy-benzyl-bromide in benzene are slowly added and the reaction proceeds from this point analogously to example 6. The thus obtained crude 2-(p-ethoxybenzyl)-5-nitro-3(2H)-oxo-2-benzofuran carboxylic acid ethyl ester gives, after crystallization from methanol, 1.4 g. of crystals, m.p. 123-124, yield 16 percent of theory.

b. 1.0 g. of 2-(p-ethoxybenzyl)-5-nitro-3(2H)-oxo-2- benzofuran carboxylic acid ethyl ester are heated to boiling under reflux for 1% hours with 27 ml. of 0.1-n sodium hydroxide. After cooling, the solution is made acid to congo red with dilute hydrochloric acid and extracted with ether. The ether extract is washed neutral, dried over sodium sulfate and evaporated. Crystallization of the residue from methanol produces 0.25 g. of Z-(p-ethoxybenzyl)-5-nitro-3(2I-I)- benzofuranone, m.p. 109-l 1 1.

c. 0.4 g. of Z-(p-ethoxybenzyl)-5-nitro-3(2H)-benzofuranone are reacted analogously to example 1c with 2.4 g. of bromoacetic acid ethyl ester and 1.0 g. of zinc wool. After purifying on 20 g. of neutral aluminum oxide, Woelm activity stage 111, 0.37 g. of 2-(p-ethoxybenzyl)-5-nitro-3-benzofuran acetic acid ethyl ester are obtained as a yellowish oil. Yield 76 percent of theory. IR in CH Cl =l735 cm."CO; 1525, 1330 cm.NO

d. 0.37 g. of 2-(p-ethoxybenzyl)-5-nitro-3-benzofuran acetic acid ethyl ester are heated to boiling point under reflux for 1% hours with 5 ml. of 0.7 molar diborane solution in tetrahydrofuran. The excess diborane is decomposed by the addition of methanol and to the resulting solution are added a few drops of a hydrogen chloride solution in methanol and the resulting mixture is heated to boiling under reflux for hour. The solvents and the boric acid methyl ester produced as byproduct are removed by evaporation in vacuo and the residue is taken up in ether and water. The ether extract is washed neutral and dried over sodium sulfate. After the evaporation of the ether, 0.33 g. of 2-(p-ethoxybenzyl)-5- nitro-3-benzofuran ethanol are obtained as a yellowish oil. Yield 97 percent of theory. [R in CH Cl,=3600 cm.l-l; 1525, 1330 cmf No e. 0.33 g. of Z-(p-ethoxybenzyl)-5-nitro-3-benzofuran ethanol are reacted analogously to example 1 e) with 0.7 g. of p-toluene sulfochloride. 0.30 g. of the crude oily p-toluenesulfonic acid-2-[2-(p-ethoxy-benzyl)-5-nitro-3-benzofuranyl]- ethyl ester are obtained. Yield 63 percent of theory. IR in CH2 =i1 4Q.1.1.&Qm- "t f. 0.30 g. of p-toluenesulfonic acid-2-[2-(p-ethoxy-benzyl)- 5-nitro-3-benzofuranyl]-ethyl ester are reacted analogously to example 1 f with 1.0 ml. of pyrrolidine.v After crystallization from acetone, 0.1 g. of l-[2-[Z-(p-ethoxybenzyl)-5-nitro-3- benzofuranyll-ethyll-pyrrolidinc-hydrochloride are obtained, m.p. 199-201. Yield 40 percent of theory.

EXAMPLE 27 0.32 g. of 2-(p-ethoxybenzyl)-5-methy1-3-benzofura.nacetic acid are dissolved in 5 ml. of absolute tetrahydrofuran. To this solution are added 0.5 ml. of thionyl chloride and the solution is refluxed for 2 hours to boiling. The solution is then concentrated by evaporation in vacuo, 5 ml. of absolute benzene are added and the solution again concentrated by evaporation, whereby adhering thionyl chloride is removed. Theobtained crude 2-(p-ethoxybenzyl)-5-methyl-3-benzofuranacetic acid chloride is dissolved in 5 ml. of absolute benzene and a solution of 1.0 ml. of piperidine in 5 ml. of benzene added dropwise. An exothermic reaction thereby occurs with precipitation of piperidine hydrochloride. After the addition is completed, the solution is boiled for a short time and filtered hot. The filtrate is washed with dilute hydrochloric acid and water, dried over sodium sulfate and concentrated by evaporation. Crystallization of the residue from ether/petroleum ether yields 0.25 g. of 2-(p-ethoxybenzyl)-5-methyl-3- benzofuran-acetic acid piperidide, m.p. 9798.

0.16 g. of 2-(p-ethoxybenzyl)-5-methyl-3-benzofuranacetic acid piperidide are dissolved in 25 ml. of ether and added dropwise to a stirred suspension of 0.5 g. of lithium aluminum hydride in 30 ml. of ether. The mixture is subsequently refluxed, while stirring, for hours. The mixture is then cooled with ice and decomposed by adding dilute hydrochloric acid dropwise. To themixture is added a solution of 5 g. of potassium sodium tartrate in 20 ml. of water. The mixture is adjusted to pH 8-9 by the addition of ammonia solution and shaken. The ethereal phase is washed with water, dried over sodium sulfate and concentrated by evaporation. The obtained crude l-[2-[2-(p-ethoxybenzyl)-5-methyl-3-benzofuranylLethyH-piperidine is converted into its hydrochloride. By this means are obtained 0.l5 g., m.p. l92-l93, yield 89 percent of theoretical value.

In an analogous mannerv is obtained from 0.32 g. of 2-(pethoxybenzyl)-5-methyl-3-benzofuranacetic acid and 0.5 ml. of thionyl chloride, the corresponding acid chloride and from the latter is obtained after treatment with 1.0 ml. of diethylamine and final processing, 0.33 g. of 2-(p-ethoxybenzyl)-5-methyl-3-benzofuranacetic acid diethylamide as colorless oil, yield 87 percent of theoretical value. [R in hydrochloride, after crystallization from acetone/ether, 0.20 g. of 2-(p-ethoxybenzyl)-3-[2-(l-diethylamino)-ethyl]-5- methyl-benzofuran hydrochloride, m.p. l39-l40. Yield 75 percent of theoretical value.

EXAMPLE 28 0.25 g. of Z-(p-ethoxybenzyl)-5-methyl-3-benzofuranacetic acid diethylamide is dissolved in 10 ml. of a 0.7-molar solution of diborane in .tetrahydrofuran and the solution is allowed to stand for 20 hours at room temperature. The excess diborane is decomposed with methanol, the solution is acidified by addition of methanolic hydrochloric acid and refluxed at boiling for half an hour. The solvent and the boric acid methyl ester, formed as byproduct, are removed by concentrating by evaporation in vacuo. The residue is taken up in water and ether, ammonia is added until the pH of the aqueous phase is about 9 and the base is extracted with ether. The ether extract is washed with water, dried over sodium sulfate and concentrated by evaporation. The obtained crude base is taken up in ether and acetone, the hydrochloride precipitated by addition of ethereal hydrochloric acid and recrystallized from acetone. 0.12 g. of 2-(p'ethoxybenzyl)-3-[2-(l-diethylamino-ethyll-S- methyl-benzofuran hydrochloride are obtained, m.p. l39-l4 0. Yield 45 percent of theoretical value.

In an analogous manner are obtained from 0.2 g. of 2-(pethoxybenzyl)-5-methyl-3-benzofuranacetic acid piperidide, after reduction with 10 ml. of a 0.7-molar solution of diborane in tetrahydrofuran and conversion of the isolated crude base into the hydrochloride, 0.14 g. of l-[2-[2-(p-ethoxybenzyl)-5- methyl-3-benzofuranyl]-ethyl]-piperidine hydrochloride, m.p. l92l93, yield 66 percent of theoretical value. 0.40 g. of 2- (p-ethoxybenzyl)-5-methyl-2,3 dihydro-3-hydroxy-3- benzofuranacetic acid-pyrrolidide are reduced with 20 ml. of a 0.7-molar solution of diborane in tetrahydrofuran and processed as described above. By this means are obtained 0.21 g. of l-[2-[2-(p-ethoxybenzyl)-5-methyl-3-benzofuranyl]- ethyll-pyrrolidine hydrochloride, m.p. l67-l69. Yield 51 percent of theoretical amount.

The pyrrolidide required as starting material is produced as follows:

0.5 g. of oily 2-(p-ethoxybenzyl)-5-methyl-2,3-dihydro-3- hydroxy-B-benzofirranacetic acid methyl ester (racemate A) dissolved in 5 ml. of benzene and to this are added 5 ml. of pyrrolidine. After refluxing for 20 hours, the solution is concentrated by evaporation in vacuo and the residue crystallized from ether. 0.4 g. of 2-(p-ethoxybenzyl)-5-methyl-2,3- dihydr0-3-hydroxy-3-benzofuranacetic acid pyrrolidide are obtained, m.p. 142143. Yield 73 percent of theoretical value.

EXAMPLE 29 a. 2.3 g. of p-toluene sulfonic acid-2-[2-(pethoxybenzyl)-5- methyl-3-benzofuranyl]-ethyl ester are reacted with 10 ml. of propylamine to the N-propyl-2-(p-ethoxybenzyl)-5-methy1-3- benzofuranethylamine. The hydrochloride of the latter melts, after recrystallization from methanol/ether, at 160-162; yield 1.5 g. percent of theoretical value.

b. 0.75 g. of N-propyl-2-(p-ethoxybenzyl)-5-methyl-3- benzofuranethylamine hydrochloride are converted, by shaking with 2N soda solution and ether, into the base which, after washing of the ether extract, drying and concentration by evaporation, is obtained as colorless oil. This is taken up in 20 ml. of ether, 0.25 ml. of pyridine and 0.25 ml. of propionic acid chloride are added and the solution is then allowed to stand for 4 hours. After washing with dilute hydrochloric acid and water, the ethereal solution is dried over sodium sulfate and concentrated by evaporation in vacuo. By this means are obtained 0.73 g. of N-propyl-2-(p-ethoxybenzyl)-5-methyl-3- benzofuranethylpropionic acid amide as colorless oil; yield percent of theoretical value. 1R in CH Cl =l 640 cm."CO.

Analogously to example 27 are obtained from 0.70 g. of N- propyl-2-(p-ethoxybenzyl)-5-methyl-3-benzofuranethylpropionic acid amide, after reduction with 2.0 g. of lithium aluminum hydride and conversion of the crude base into the hydrochloride, 0.65 g. of N,N-dipropyl-2-(p-ethoxybenzyl)-5- methyl-3-benzofuranethylamine hydrochloride, m.p. l06-10 8. Yield 86 percent of theoretical value.

In an analogous manner is obtained, from 3.3 g. of 2-(pisopropoxybenzyl)--methyl-3-benzofuranacetic acid and 5.16 ml. of thionyl chloride, the acid chloride and from this, after reaction with 10 ml. of piperidine and after crystallization from ether/petroleum ether, 2-(p-isopropoxybenzyl)-5- methyl-3-benzofuranacetic acid piperidide, m.p. 81-82. Yield 3.75 g., 95 percent of theoretical value; and with 10 ml. of di-n-propylamine is obtained the oily N,N-dipropyl-2-(p isopropoxybenzyl)-5-met.hyl-3-benzofuranacetic acid amide. Yield 3.8 g., 97 percent of theoretical value and from 10 ml. of pyrrolidine are obtained after crystallization from ether/petrolether 3.44 g. of the 2-(p-isopropoxy benzyl)-5- methyl-3-benzofuran acetic acid pyrrolidide, m.p. l01-l03. Analogously to example 27 are obtained from 3.75 g. of 2-(pisopropoxybenzyl)-5-methyl-3-benzofuranacetic acid piperidide, after reduction with 10 g. of lithium aluminum hydride and conversion of the crude base into the hydrogen sulfate-and after crystallization from acetone 3.55 g. of l- [2-[2-(p-isopropoxybenzyl)-5-methyl-3-benzofuranyl]-ethyl]- piperidine hydrogen sulfate, m.p. l7 l-172 (yield 79 percent of theoretical value) and in the same manner, from 3.8 g. of N,N-dipropyl-2-(p-isopropoxybenzyl)-5-methyl-3-benzofuranacetic acid-after crystallization from acetone/ether, the N,N-dipropyl-2-(p-isopropoxybenzyl)-5-methyl-3-benzofuranethylamine hydrochloride, m.p. 163-l64; yield 2.97 g., 74 percent of theoretical value. In a similar manner are obtained from 3.40 g. of 2-(p-isopropoxybenzyl)-5-methyl-3- benzofuranacetic acid pyrrolidide, m.p. 10l-102, after reduction with 10 g. of lithium aluminum chloridefrom acetone/ether-2.7 g. l-[ 2-[2-( pJsopropoxybenzyD-S- methyl-3-benzofuranyl]-ethyl]-pyrrolidine hydrochloride, m.p. l91l92; yield 75 percent of theoretical value.

in an analogous manner is obtained from 3.85 g. of 2-(pethoxybenzyl)-5-chloro-3-benzofuranacetic acid and 6.1 ml. of thionyl chloride, the acid chloride and from the latter, after treatment with 12.3 ml. of pyrrolidine-after final processing and crystallization from chloroform/petroleum ether, 3.65 g. of 2-(p-ethoxybenzyl)-5-chloro-3-benzofuranacetic acid pyrrolidide, m.p. 128-129 (yield 81 percent of theoretical value). In like manner is obtained, after reaction of the acid chloride with diethylamine, the oily 2-(p-ethoxybenzy1)-5- chloro-3-benzofuranacetic acid diethylamide; yield 4.2 g. (93 percent of theoretical value). IR in CH Cl ==1640 cm. CO. Furthermore, analogously to example 27, are obtained from 3.85 g. of 2-(p-ethoxybenzyl)-5-chloro-3-benzofuranacetic acid pyrrolidide, after reduction with 5.0 g. of lithium aluminum hydride and conversion of the crude base into the hydrochloride after crystallization from acetone/water, 3.22 g. of l-[2-[2-(p-ethoxybenzyl)-5-chloro-3-benzofuranyl]-ethyl]- pyrrolidine hydrochloride, m.p. 196 -l97; yield 79 percent of theoretical value.

in the same manner is obtained from 2.1 g. of 2-(p-ethoxybenzyl)-5-chloro-3benzofuranacetic acid diethylamide, after reduction with 3.0 g. of lithium aluminum hydride and conversion of the crude base into the hydrochloride-after crystallization from acetone/ether-, 1.41 g. of 2-(p-ethoxybenzyl)- 5-chloro-3-[2-diethylamino)-ethyl]-benzofuran hydrochloride, m.p. 129-l 30; yield 64 percent of theoretical value.

In an analogous manner is obtained from 0.34 g. of 2-(pethoxybenzyl)-5-methoxy-3-benzofuranacetic acid and 0.5 ml. of thionyl chloride, the acid chloride, which, after treatment with 1.0 ml. of diethylamine and after processing as described above, yields I 0.36 g. of Z-(p-ethoxybenzyD-S- methoxy-3-benzofuranacetic acid diethylamide as colorless oil; yield 91 percent of theoretical value. lR in CH,C1,==1640 cm. CO. Moreover, 0.26 g. of 2-(p-ethoxybenzyl)-3-[2-(1- diethylamino)-ethyl]-5-methoxybenzofuran hydrochloride,

m.p. l23 124; yield 70 percent of theoretical value, is obtained from 0.35 g. of 2-(p-ethoxybenzyl)-5-methoxy-3- benz ofuranacetic acid diethylamide, after reduction with 0.8 g. of lithium aluminum hydride and conversion of the crude base into the hydrochloride, after crystallization from acetone/ether.

EXAMPLE 30 a. 2.5 g. of 1-(p-ethoxyphenyl)-6-methyl-3,4- dihydrobenzofuro[2.3lpyridine are heated under nitrogen with 10 ml. of hydrazine hydrate in 30 ml. of diethylene glycol for 10 minutes to 200, then cooled and 5.5 g. of potassium hydroxide are added. The reaction mixture is subsequently heated for 2 hours to 200 and, with initial foaming, water vapor and nitrogen escape during this period. After allowing the reaction mixture to cool, it is poured into water and the base is extracted with ether. The ether solution, washed with water and dried over sodium sulfate yields, after concentrating by evaporation, 2.3 g. of colorless oil which, after a short time, solidifies to give fibrous crystals of the 2-(pethoxybenzyl)-5 methyl-3-benzofuranethylamine, m.p. 49-50; yield 91 percent of theoretical value. By adding hydrochloric acid gas in ether, the hydrochloride is obtained which, after recrystallization from methanol/ether, melts at l76-l 77'.

b. To a solution of 0.30 g. of 2-(p-ethoxybenzyl)-5-methyl-3 -benzofuranethylamine in 5 ml. of acetonitrile are added 0.20 g. of diisopropylamine and 0.34 g. of l,5-dibromopentane. Refluxing is carried out for 24 hours, the acetonitrile removed in vacuo and the residue is taken up with dilute soda solution and ether. The ether extract is extracted with dilute hydrochloric acid, the acid extracts are made alkaline with soda solution and the thereby oily precipitated base is extracted with ether. The ethereal extract, washed with water, is dried over sodium sulfate and concentrated by evaporation in vacuo. The residual crude l-[2-[2-(p-ethoxybenzyl)-5- methyl-3-benzofuranyl]-ethyl]-piperidine is dissolved in ether and a small excess of etheral hydrochloric acid is added. From the precipitated hydrochloride are obtained, after recrystallization from acetone, 0.20 g. of l-[2[2-(p-ethoxybenzyl)-5- methyl-3-benzofuranyl]-ethyl]-piperdine hydrochloride, m.p. 192-193; yield 48 percent of theoretical value.

In an analogous manner are obtained from 0.30 g. of 2-(pethoxybenzyl)5-methyl-3-benzofuran ethylamine and 0.32 g. of 1,4-dibromobutane, after crystallization from acetone/ether, 0.21 g. of l-[2-[2-(p-ethoxybenzyl)-5-methyl- 3-benzofuranyl]-ethyl]-pyrrolidine hydrochloride, m.p. 167-l69; yield 52 percent of theoretical value.

Furthermore, from 0.3 g. of 2-(p-ethoxybenzyl)-5-methyl-3 -benzofuranethylamine and 0.36 g. of propyl bromide are obtained, after crystallization from acetone/ether, 0.18 g. of N,N-dipropyl-2-(p-ethoxybenzyl)-5-methyl-3-benzofuranethylamine hydrochloride, m.p. l06-l07; yield 42 percent of theoretical value, and from 0.30 g. of 2-(p-ethoxybenzyl)-5-methyl-3-benzofuranethylamine and 0.32 g. of ethylbromide are obtained, after crystallization from acetone/ether, 0.24 g. of N,N-diethyl-2-(p-ethoxybenzyl)-5- methyl-3-benzofuranethylamin e hydrochloride, m.p. 139-l4 0; yield 60 percent of theoretical value.

EXAMPLE 31 1.0 g. of ptoluenesulfonic acid-2-[2-(p-ethoxybenzyl)-5- chloro-3-benzofuranyl]-ethy1 ester is heated in a pressure vessel with 4.0 g. of liquid ammonia for 6 hours to After cooling to room temperature, the ammonia is allowed to escape and the residue taken up in water and ether. The ether extract is washed with water and extracted with dilute hydrochloric acid. The acid extracts are adjusted to pH 9 with concentrated ammonia solution and the precipitated base is extracted with ether. The ether extract yields, after washing, drying over sodium sulfate and concentrating by evaporation, 0.7 g. of oily 2-(p-ethoxybenzyl)-5-chloro-3-benzofuranethylamine. By adding hydrochloric acid gas in ether is obtained the hydrochloride which, after recrystallization from acetone/ether, melts at 2l6-2l9; yield 75 percent of theoretical value.

From 0.33 g. of 2-(p-ethoxybenzyl)-5-chloro-3-benzofuranethylamine and 0.33 g. of ethylbromide are obtained, afler crystallization from acetone/ether, 0.25 g. of N,Ndiethyl-2- (p-ethoxybenzyl)--chloro-3-benzofuranethylamine hydrochloride, m.p. ,l29-l 30; yield of 59 percent of theoretical value.

In an analogous manner are obtained from 0.33 g. of 2-(pethoxy)-5-chloro-3-benzofuranethylamine and 0.34 g. of 1,5- dibromopentane, after crystallization from dioxane/water, 0.19 g. of 1-[2-[2-(p-ethoxybenzyl)-5-chloro-3-benzofuranyl]-ethyl]-piperidine hydrochloride, m.p. 2l2213; yield 44 percent of theoretical value. Furthermore, from 0.33 g. of 2- (p-ethoxy)-S-chloro-3-benzofuranethylamine and 0.32 g. of 1,4-dibromobutane are obtained, after crystallization from acetone/water, 0.22 g. of l-[2-[2-(p-ethoxybenzyl)-5-chlor0- 3-benzofuranyl]-ethyl]-pyrrolidine hydrochloride, m.p. l96197; yield 53 percent of theoretical value.

EXAMPLE 3 2 From 2.4 g. of p-toluenesulfonic acid-2-[2-(p-isopropoxybenzyl)-5-methyl-3-benzofuranyll-ethylester are obtained, after reaction with l0.0 g. of ammonia, 1.17 g. of 2-(pisopropoxybenzyl)-5-methyl-3-benzofuranethylamine as colorless oil (yield 72 percent of theoretical value). From 0.31 g. of this oil and 0.34 g. of l,5-dibromopentane are obtained, after conversion into the hydrogen sulfate and crystallization from acetone, 0.25 g. of 1-[2-[2-(p-isopropoxybenzyly5- methyl-3-benzofuralyl -ethyl ]-piperidine hydrogen sulfate, m.p. l7 l-l 72"; yield 50 percent of theoretical value.

ln an analogous manner from 0.31 g. of 2-(p-isopropoxybenzyl)-5-methyl-3-benzofuranethylamine and 0.32 g. of l,4-dibromobutane are obtained, after crystallization from acetone/ether, 0.22 g. of l-[2[2-(p-isopropoxybenzyl)-5- methyl-3-benzofuranyl]-ethyl]-pyrrolidine hydrochloride, m.p. l9 ll92; yield 53 percent of theoretical value.

in the same manner are obtained with 0.36 g. of propylbromide, 0.20 g. of N,Ndipropyl-2-(p-isopropoxybenzyl)-5 methyl-3-benzofuranethylamine hydrochloride, m.p.. l63-16 4; and from 2.4 g. of p-toluenesulfonic acid-2-[2-(p-ethoxybenzyl)-5-methoxy-3-benzofuranyll-ethyl ester are obtained, after reaction with 10.0 g. of ammonia, 1.2 g. of 2-(p-ethoxybenzyl)-5-methoxy-3-benzofuranethylamine as oil; yield 74 percent of theoretical value (lR in Nujol*(*Registered Trade Mark) =3380 cmfl Nl-l 1.2 g. of this oil are reacted with 1.30 g. of ethylbromide and, after crystallization from acetone/ether, 0.95 g. of 2-(p-ethoxybenzyl)-5-methoxy-3-[2- (diethylamine)-ethyl]-3-benzofuran hydrochloride are produced, yield 62 percent of theoretical value, m.p. l23l2 4.

EXAMPLE 3 3 a. To 4.2 g. of 5-methyl-3-benzofuranethanol are added 20 ml. of pyridine and 5 ml. of aceticanhydride. After standing for 20 hours at room temperature, the solution is poured into water and stirred. After half an hour, the precipitated oil is separated by decanting and is taken up in ether. The ether solution is washed with dilute hydrochloric acid, water and sodium bicarbonate solution, dried over sodium sulfate and concentrated by evaporation. 4.9 g. of crude acetic acid 2-(5- methyl-3-benzofuranyl)-ethyl ester are obtained as yellowish oil; yield 89 percent of theoretical value.

b. 4.9 g. of crude acetic acid 245-methyl-3-benzofuranyl)- ethyl ester and 4.4 g. of p-ethoxybenzoyl chloride are dissolved in 25 ml. of carbon disulfide and, after cooling the solu tion to 0, 6.5 g. of tin tetrachloride are added dropwise, while stirring and in the course of half an hour. The solution thereby tums brown and a precipitate is formed. The mixture is stirred for a further 6 hours at room temperature. After decomposing with water, the reaction vessel is rinsed with 100 ml. of

chloroform into a separating funnel.v The yellowish organic phase is washed with water, dried over sodium sulfate and concentrated by evaporation. Crystallization of the residue from methanol yields 5.5 g. of acetic acid 2-[5-methyl-2-(pethoxybenzoyl)-3-benzofuranyl]-ethyl ester, m.p. 94-95; yield 67 percent of theoretical value.

c. 5.3 g. of acetic acid 2-[S-methyl-Z-(p-ethoxybenzoyl)-3- benzofuranyll-ethyl ester are refluxed to boiling with 0.8 g. of sodium hydroxide in 30 ml. of 70 percent ethanol for 2 hours in the reflux condenser. Water is gradually added to the hot solution, whereupon crystallization occurs. After recrystallization from methanol/water are obtained 4.3 g. of 5-methyl-2- (p-ethoxybenzoyl)r3-benzofuranethanol, m.p. l 28-l 30; yield 95 percent of theoretical value.

d. 4.3 g. of 5-methyl-2-(p-ethoxybenzoyl)-3-benzofuranethanol are dissolved in 45 ml. of absolute pyridine and, after cooling the solution to -l5, 7.0 g. of ptoluenesulphochloride are added in portions. After standing for 18 hours at 0", the solution is poured into ice water, the precipitated oil separated and triturated. Crystallization occurs after some time. Recrystallization from chloroform/ether yields 5.4 g. of 5-methyl-2-(p-ethoxybenzoyl)-3-benzofuranethyl-ptoluenesulfonic acid ester, m.p. 125-l26; yield 65 percent of theoretical value.

e. 2.5 g. of p-toluenesulfonic acid ester, from (d), are refluxed to boiling with 25 ml. of pyrrolidine for 5 hours in the reflux condenser. The solution is then concentrated by evaporation in vacuo and the residue crystallized from water. After recrystallization from methanol/acetone, 2.0 g. of l-[2- [2-( p-ethoxybenzoyl )-5-methyl-3-benzofuranyl]-ethyl ]-pyrrolidine hydrochloride, m.p. 202-205 (decomposition) are obtained; yield percent of theoretical value.

f. 2.5 g. of p-toluenesulfonic acid ester, from (d), are refluxed in the reflux condenser with 25 ml. of piperidine for 5 hours to boiling. The solution is concentrated by evaporation in vacuo, 20 ml. of benzene are added and again concentrated by evaporation. The residue is taken up in water and ether. The ethereal phase is repeatedly washed with water and then extracted 3 times using 5 ml. of 1N hydrochloric acid each time. The acid extracts are adjusted to pH 9 with concentrated ammonia and the thereby oily precipitated base is extracted with ether. The ethereal extract, washed with water, is dried over sodium sulfate and concentrated by evaporation in vacuo. The oily residue is dissolved in ether and some acetone and a small excess of dilute ethereal sulfuric acid is added. The precipitated oil crystallizes upon triturating. After recrystallization from methanol/acetone are obtained 2.1 g. of l-[ 2-[2- (p-ethoxybenzoyl)-5-methyl-3-benzofuranyl]-ethyl]- piperidine hydrogen sulfate, m.p. l50-15 1; yield 80 percent of theoretical value.

g. 0.7 g. of p-toluenesulfonic acid ester, from (d), are refluxed to boiling with 20 ml. of diethylamine for 48 hours. The procedure was otherwise analogous to that described in (f), 0.4 g. of l[2-[2-(p-ethoxybenzoyl)-5-methyl-3-bensofuranyl]-ethyl]-diethylamine hydrogen sulfate, m.p. l-l97, are obtained; yield 56 percent of theoretical value.

h. Analogously to (f), 6.0 g. of p-toluenesulfonic acid ester from (d) are reacted with 60 ml. of di-n-butylamine. The obtained crude base is converted, analogously to (e), into the hydrochloride. After crystallization from acetone, 4.6 g. of l- [2-[2-(p-ethoxybenzoyl)-5-methyl-3-benzofuranyl]-ethyl]-din-butylamine hydrochloride, m.p. l88l90, (yield 77 percent of theoretical value) are obtained.

i. 0.75 g. of l-[2-[2-(p-ethoxybenzoyl)-5-methyl-3-benzofuranyl]'ethyl]-pyrrolidine hydrochloride are converted, by shaking with 2N soda solution, into the base and the latter is isolated by extraction with ether, washing of the ethereal phase with water, drying over sodium sulfate and concentrating by evaporation.

To the oily base are added 7 ml. of a 0.7-molar solution of diborane in tetrahydrofuran. The mixture is maintained for 20 hours at room temperature. The solution is decomposed by addition of methanol, made acidic with ethereal hydrochloric acid and refluxed for one hour. The solution is then concentrated by evaporation in vacuo, methanol is added and again the solution is concentrated by evaporation. The residue is taken up in water, the obtained cloudy solution made strongly alkaline with concentrated ammonia and extracted with ether. The ether phase is repeatedly washed with water, dried over sodium sulfate and concentrated by evaporation. The residue is taken up with methanol, a small excess of methanolic hydrochloric acid is added and the solution boiled up with some animal charcoal. It is then filtered and the filtrate concentrated by evaporation in vacuo. The residue crystallizes upon triturating with acetone. After recrystallizing from methanol/acetone, 0.58 g. of l-[2-[2-p-ethoxybenzyl)-5- methyl-B-benzofuranyl]-ethyl]-pyrrolidine hydrochloride, m.p. l67-l69, are obtained; yield 84 percent of theoretical value.

j. Analogously to (i), from 2.0 g. of l-[2-[2-(p-ethoxybenzoyl)--methyl-3-benzofuranyl]-ethyl]-piperidinc hydrogen sulfate are after conversion into the base and reduction of the latter with 20 ml. of a 0.7-molar solution of diborane in tetrahydrofuran, 1.34 g. of l-[2-[2-(p-ethoxybenzyl)-5-methyl-3-benzofuranyl]-ethyll-piperidine hydrochloride, m.p. 192193; yield 79 percent of theoretical value.

it. Analogously to (i), from 2.0 g.' of 1-[2-[2-(p-ethoxybenzoyl)-5-methyl-3-benzofuranyl]-ethyl]-diethylamine hydrogen sulfate are produced, after conversion into the base and reduction of the latter with 20 ml. of a 0.7-molar solution of diborane in tetrahydrofuran, 1.23 g. of l-[2-[2-(p-ethoxybenzyl)-5-methyl-3-benzofuranyl]-ethy1]-diethylamine hydrochloride, m.p. 139 140; yield 72 percent of theoretical value.

EXAMPLE 34 1.0 g. of 1-[2-[2-(p-ethoxybenzoyl)-5-methyl-3-benzofuranyl]-ethyl]-pyrrolidine-hydrochloride is dissolved in 20 ml. of diethylene glycol, treated with 4.5 ml. of hydrazine hydrate and heated under an atmosphere of nitrogen in a distillation apparatus until the temperature of the reaction mixture reaches 195. The temperature is kept at 195 for minutes, then allowed to cool to 150, and 2.2 g. of potassium hydroxide are added. The generation of nitrogen is brought to completion by heating for 2 hours at 200. The reaction mixture is then cooled, poured into water and extracted with ether. The ether extract is washed several times with water, dried over sodium sulfate, and concentrated by evaporation. The residue is taken up with ether and a small amount of acetone, and a slight excess of ethereal hydrochloric acid is added. Upon trituration, 0.7 g. of l-[2-[2-(p-ethoxybenzyl)-5- methyl-S-benzofuranyl]-ethyl]-pyrrolidine-hydrochloride having a melting point of 167 469, crystallize. Yield: 81

percent of theory.

In an analogous manner, the following are obtained:

from 2.0 g. of 1-[2-[2-(p-ethoxybenzoyl)-5-methyl-3-benzofuranyl]-ethyllpiperidine-hydrogen sulfate, by treating with 8 ml. of hydrazine hydrate in 40 ml. of diethylene glycol and 4.4 g. of potassium hydroxide, 1.35 g. of l-[2-[2-(p-ethoxybenzyl)-5-methyl-3-benzofuranyl]-ethyllpiperidine-hydrochloride, m.p. 1922. Yield: 80 percent of theory; from 1.1 g. of l-[2-[2-(p-ethoxybenzoyD-S- methyl-3-benzofuranyl]-ethyl]-diethylamine-hydrogen sulfate, 0.71 g. of l-[2-[2-(p-ethoxybenzyl)-5-methyl-3- benzofuranyl]-ethyll-diethylamine-hydrochloride, m.p. 139-l40. Yield: 75 percent of theory; and

from 4.5 g. of l-[Z-l2-(p-ethoxybenzoyl)-5-mcthyl-3- benzofuranyH-ethyl]-di-n-butylamine-hydrochloride, 2.0 g. of 1-[2-[Z-(p-ethoxybenzyl)-5-methyl-3-benzofuranyl]-ethyl]- din'butylamine-hydrochloride, m.p. l06l07. Yield: 45 percent of theory.

EXAMPLE 3s a. Analogously to example 33(b), 12.2 g. of crude acetic acid 2-(S-methyl-B-benzofuranyl)-ethyl ester are reacted with 12.5 g. of p-butoxybenzoyl chloride and 16.1 g. of tin tetrachloride in 60 ml. of carbon disulfide. Crystallization of the crude product from methanol yields 17.0 g. of acetic acid 2[5-methyl-2-(p-butoxybenzoyl)-3-benzofuranyl]-ethyl ester m.p. 76-77. Yield 78 percent of theory.

b. Analogously to example 33(c), 17.0 g. of the ester obtained in (a), are hydrolized with 2.4 g. of sodium hydroxide in ml. of 70 percent ethanol. Upon the addition of water, the product crystallizes. Recrystallization from methanol yields 14.0 g. of 5-methyl-2-(p-butoxy-benzoyl)-3-benzofuranethanol, m.p. 12 l-122. Yield 92 percent of theory.

c. Analogously to example 33(d), 14.0 g. of 5-methyl-2-(pbutoxybenzoyl)-3-benzofuran-ethanol in 125 ml. of absolute pyridine are reacted with 25 g. of p-toluene-sulfochloride. After crystallization from ether/petroleum ether, 17.5 g. of ptoluene-sulfonic acid -2-[5-methyl-2-(p-butoxybenzoyl)3- benzofuranyll-ethyl ester m.p. 100-l0l are obtained, yield 87 percent of theory.

d. Analogously to example 33(c), 9.0 g. of p-toluene-sulfonic acid-2-[5-methyl-2-(p-butoxybenzoyl)-3-benzofuranyl1' ethyl ester are treated with 40 m1. of pyrrolidine. Crystallization from water/acetone yields 6.2 g. of l-[2-[2-(p-butoxybenzoyl)-5-methyl-3-benzofuranyl]-ethyl]-pyrrolidinehydrochloride, m.p. 2l6-218.

e. Analogously to example 33(i), from 1.0 g. of l-[2-[2-(pbutoxybenzoyl)-5-methyl-3-benzofuranyl]ethyl]-pyrrolidine hydrochloride, there is obtained 0.58 g. of l[2-[2-(p-butoxybenzyl)-5-methyl-3-benzofuranyl]-ethyl]-pyrrolidinehydrochloride, m.p. 164-166. Yield: 60 percent of theory.

EXAMPLE 36 6-methyl-3-benzofuran acetic acid is produced according to the article by B. B. Dey and K. Radhabai, J. ind. chem. Soc., 11, 635 (1934).

22.0 g. of 6-methyl benzofuran acetic acid are reduced analogously to example 1(c) with 12 g. of lithium aluminum hydride. 18.0 g. of 6-methy1-3-benzofuran-ethanol are obtained as colorless oil. Yield 96 percent of theory.

Analogously to example 33(a), 18.5 g. of 6-methyl-3- benzofuran-ethanol are esterified with 25 m1. of acetic anhydride in 90 ml. of pyridine. 20 g. of crude acetic acid-2-(6- methyl-3-benzofuranyl)-ethyl ester are obtained as colorless oil. Yield 88 percent of theory.

Analogously to example 33(b), 19.5 g. of acetic acid 2-( 6- methyl-3-benzofuranyl)-ethyl ester are reacted with 17.6 g. of p-ethoxybenzoyl chloride and 26 g. of tin tetrachloride. After crystallization from methanol, 28.0 g. of acetic acid-2-[-6- methyl-2-(p-ethoxybenzoyl)-3-benzofuranyl]-ethy1 ester, m.p. 9192 are obtained. Yield 85 percent of theory.

Analogously to example 33(c), 28.0 g. of the ester obtained in the previous step are hydrolized with 4.2 g. of sodium hydroxide in ml. of 70 percent ethanol. After the addition of water, the product precipitates as crystals. Recrystallization from methanol yields 23.8 g. of 6-methyl-2-(p-ethoxybenzoyl)-3-benzofuran-ethanol, m.p. l05-l06. Yield: 96 percent of theory.

Analogously to example 33(d), 23.5 g. of ethanol obtained in the previous step are reacted with 6 g. of p-toluene sulfochloride in 224 ml. of absolute pyridine. Crystallization from ether/petroleum ether yields 28.5 g. of p-toluene-sulfonic acid-2-[ 6-methyl-2-( pethoxybenzoyl )-3-benzofuranyl ethyl ester, m.p. 97-98. Yield: 82 percent of theory.

Analogously to example 33(f), 6.0 g. of p-toluene-sulfonic acid ester obtained in the previous step are reacted with 60 ml. of pyrrolidine. The crude base obtained is converted, analogously to example 33(e) to the hydrochloride. After crystallization from acetone/ether, 4.4 g. of l-[2-[2-(p-ethoxybenzoyl) 6-methyl-3-benzofuranyl]-ethyll-pyrrolidinehydrochloride, m.p. 203204, are obtained. Yield: 86 percent of theory.

Analogously to example 33(i), from 4.3 g. of 1-[2-[2-(pethoxy'oenzoyl)-6-methyl-3-benzofuranyl]-ethyl]-pyrrolidinehydrochloride, there are obtained 3.1 g. of l-[2[2-(p-ethoxybenzyl)-6-methyl-3-benzofuranyl]-ethyl]-pyrrolidinehydrochloride, m.p. l79-l80. Yield 75 percent of theory.

EXAMPLE 37 a. 10.0 g. of 3-ethyl-phenol are introduced into a mixture of 20.0 g. of acetone dicarboxylic acid and 30 m1. of concentrated sulfuric acid which has been cooled to After addition of a further ml. of concentrated sulfuric acid, the reaction mixture is kept for 18 hours at 0 and then poured into 500 ml. of ice water. The precipitate obtained is removed by filtration and then extracted a number of times with cold, saturated sodium bicarbonate solution. From the extracts, which have been clarified by filtration and acidified with concentrated hydrochloric acid to pH 1, a crystalline precipitate is obtained. Recrystallization from ethanol water yields 5.0 g. of 7-ethyl-4-coumarin acetic acid, m.p. 187-l 88. Yield: 26 percent of theory.

b. 20.0 g. of 7-ethyl-4-coumarin acetic acid are suspended in 90 ml. of glacial acetic acid and treated all at once with a solution of 18 g. of bromine in 90 ml. of glacial acetic acid. After heating for a short time on a boiling water bath, a yellow solution is obtained, which, upon cooling, yields crystalline 7- ethyl-4-cumarin-1'-bromoacetic acid. The crystals are removed by filtration and extracted a number of times with cold sodium bicarbonate solution. The extracts are adjusted to pH 1 with concentrated hydrochloric acid, whereby the product precipitates as crystals. Removal by filtration and crystallization from ethanol yields 20.0 g. of 7-ethyl-4-coumarin-l '-bromoacetic acid, m.p. l62164. Yield: 75 percent of theory.

c. 20.0 g. of 7-ethyl-4-coumarin-l-bromoacetic acid are suspended in 100 ml. of xylene and the mixture is refluxed for 24 hours. The acid dissolves and carbon dioxide escapes. The reaction mixture is cooled, whereby crude 7-ethyl-4- bromomethyl coumarin crystallizes. After recrystallization from alcohol, 14.0 g. of the coumarin, having a melting point of l57l58, are obtained. Yield: 82 percent of theory.

d. 14.0 g. of 7-ethyl-4-bromomethyl coumarin are treated with 100 ml. of 30 percent potassium hydroxide solution and the mixture is heated to boiling. As soon as a clear solution is obtained, it is cooled and, with the addition of ice, is adjusted to pH 1 with concentrated hydrochloric acid. The precipitate is removed by filtration and then extracted with sodium bicarbonate solution. The extracts are adjusted to pH 1 with concentrated hydrochloric acid, and the crystalline precipitate obtained is removed by filtration. Crystallization of the product from ether/petroluem ether yields 4.3 g. of 6-ethyl-3- benzofuran-acetic acid, m.p. 75-76. Yield: 40 percent of theory.

e. 4.3 g. of 6-ethyl-3-benzofuranacetic acid are reduced with 2.5 g. of lithium aluminum hydride in 70 ml. of ether. 4.0 g. of 6-ethyl-3-benzofuran-ethanol are obtained as colorless oil; yield quantitative.

f. From 4.0 g. of 6-ethyl-3-benzofuranethanol are obtained, analogously to example 33a, 4.2 g. of acetic acid-2-( 6-ethyl-3- benzofuranyl)-ethyl ester as colorless oil; yield 86 percent of theoretical value.

g. Analogously to example 33b, 4.2 g. of acetic acid-2-(6- ethyl 3-benzofuranyl)-ethyl ester are treated with 3.5 g. of pethoxybenzoyl chloride and 5.0 g. of tin tetrachloride. By this means are obtained 6.2 g. of oily acetic acid-2-[6-ethyl-2-(pethoxybenzoyl)-3-benzofuranyl]-ethyl ester; yield 90 percent of theoretical value.

11. From 6.2 g. of acetic acid ester obtained in the previous step are obtained, analogously to example 330, 4.5 g. of crude oily 6-ethyl-2-(p-ethoxybenzoyl)-3-benzofiiranethanol; yield 82 percent of theoretical value.

i. From 4.5 g. of crude 6-ethyl-2-(p-ethoxybenzoyl)-3- benzofuranethanol are obtained, analogously to example 33(d) and after crystallization from ether, 3.0 g. of p-toluene sulfonic acid-2-[6-ethyl-2-(p-ethoxybenzoyl)-3-benzofuranyl] -ethyl ester, m.p. 86-87; yield 46 percent of theoretical value.

j. From 2.7 g. of p-toluenesulphonic acid ester obtained in the previous step is obtained, analogously to example 33(f), by reaction with 27 ml. of pyrrolidine and conversion of the obtained crude base 1 into the hydrochloride and after recrystallization form acetone, 1.0 g. of l-[2-[2-( p-ethoxybenzoyl)-6-ethyl-3-benzofuranyl]-ethyl]-pyrrolidine hydrochloride, m.p. 192-l93; yield 43 percent of theoretical value.

it. From 1.0 g. of l-[2-[2-(p-ethoxybenzoyl)-6-ethyl-3- benzofuranyl]-ethyl]-pyrrolidine hydrochloride are obtained, analogously to example 34, v 0.6 g. of 1-[2-[2-(p-ethoxybenzyl)-6-ethyl-3-benzofuranyl]-ethyl]-pyrrolidine hydrochloride, m.p. l63-164; yield 62 percent of theoretical value.

From 6.0 g. of p-toluenesulfonic acid-2-[6-methyl-2-(pethoxybenzoyl)-3-benzofuranyl]-ethyl ester (obtained analogously to (a)-(i)) and 60 ml. of diethylamine is obtained, the crude base and this is converted into the hydrochloride. After crystallization from acetone are obtained 3.7 g. of l-[2- [2-( p-ethoxybenzoyl )-6-methyl-3-benzofuranyl j-ethyl diethylamine hydrochloride, m.p. 185-l87; yield 69 percent of theoretical value.

From 3.7 g. of 1-[2-[2-(p-ethoxybenzoyl)-6-methyl-3- benzofuranyl]-ethyl]-diethylamine hydrochloride are obtained, by reduction with diborane and after crystallization from acetone/ether, 2.0 g. of 1-[2-[ 2-(p-ethoxybenzyl)-6- methyl-3-benzofuranyl]-ethyl]-diethylamine hydrochloride, m.p. l35-l37; yield 56 percent of theoretical value.

EXAMPLE 38 To a solution of 90 g. of 5-chloro-3(2H )-benzofuranone and 90 g. of cyanoacetic acid ethyl ester in 150 ml. of toluene are added 3 ml. of pyrrolidine. After the exothermic reaction has ceased, the mixture is refluxed for 24 hours, whereby the azeotropically distilled water, is removed by means of a waterseparater.

After the reaction is finished, the toluene and the excess cyanoacetic acid ethyl ester are distilled off in vacuo. The darkly colored residue is refluxed with a solution of g. of sodium hydroxide in 800 ml. of percent ethanol for 48 hours. Initially, crystals of 5-chloro-3-benzofuranacetamide hereby precipitate, which for the most part gradually go into solution again. Finally, the ethanol is removed in vacuo and the mixture remaining is extracted with water. The filtered alkaline extracts are adjusted to pH 1 with concentrated hydrochloric acid, while cooling with ice, and extracted with ether. The ethereal extracts are washed with water, dried over sodium sulfate and concentrated by evaporation. The obtained crude 5-chloro-3-benzofuranacetic acid yields, after twice crystallizing from methanol/water, 31.5 g. of crystals, m.p. l40-141 (in a sealed tube); yield 28 percent of theoretical value.

4.2 g. of 5-chloro-3-benzofuranacetic acid are reduced with 3.0 g. of lithium aluminum hydride. 3.15 g. of 5-chloro-3 benzofuranethanol are obtained as oil; yield 80 percent of theoretical value. 1R in CH Cl =3590 cm. OH.

1 1.2 g. of S-chloro-3-benzofuranethanol are acetylated with 13.6 ml. of acetic anhydride, 13.0 g. of acetic acid-2-(5- chloro-3-benzofuranyl)-ethyl ester are obtained as oil; yield percent of theoretical value. (1R in CH C1 =1730 cm. CO).

6.5 g. of this acetic ester are reacted with 7.2 g. of p-ethoxybenzoyl chloride and 8.0 g. of tin tetrachloride. The obtained oil yields, from methanol, 3.2 g. of acetic acid-2-[2-(p-ethoxybenzoyl)-5-chloro-3-benzofuranyl1-ethyl ester, m.p. 1 l8-1l 9; yield 29 percent of theoretical value.

3.2 g. of acetic acid-2-[2(p-ethoxybenzoyl)-5-chloro-3- benzofuranyH-ethyl ester are hydrolyzed with 0.7 g. of sodium hydroxide in 35 ml. of 85 percent ethanol. The crystals obtained upon cooling are filtered off and recrystallized from alcohol/water. 1.7 g. of 2-(p-ethoxybenzoyl)-5chloro-3- benzofuranethanol, m.p. l20-l2l, are obtained; yield 60 percent of theoretical value.

From 1.2 g. of this alcohol are obtained, after reaction with 2.0 g. of p-toluenesulfochloride and crystallization from ether, 1.7 g. of p-toluene-sulfonic acid-2-[2-(p-ethoxybenzoyl)-5- chloro-3-benzofuanyll-ethyl ester, m.p. l28-129; yield 97 percent of theoretical value.

1.7 g. of this p-toluenesulfonic acid ester are reacted with ml. of pyrrolidine. After conversion of the isolated crude base into the hydrochloride and crystallization from methanol/water, 1.2 g. of l-[2-[2-(p-ethoxybenzoyl)-5- chloro-3-benzofuranyl]-ethyl]-pyrrolidine hydrochloride, m.p. l88-190, are obtained; yield 88 percent of theoretical value.

Analogously to example 34, 1.2 g. of l-[2-[2-(p-ethoxybenzoyl)-5-chloro-3-benzofuranyl]-ethyl]-pyrrolidine hydrochloride are converted into the free base and the latter is reduced with 4.5 ml. of hydrazine hydrate. After crystallization from acetone/water is obtained 1.0 g. of l-[2-[2-(pethoxybenzyl)-5-chloro-3-benzofuranyl]-ethyl]-pyrrolidine hydrochloride, m.p. l96-197; yield 86 percent of theoretical value.

EXAMPLE 39 a. 63.5 g. of acetic acid-2-(5-methyl-3-benzofuranyl)-ethyl ester are reacted with 61 g. of p-isopropoxybenzoyl chloride and 84 g. of tin tetrachloride. After crystallization from methanol are obtained 76 g. of acetic acid-2-[2-(p-isopropoxybenzoyl)-5-methyl-3-benzofuranyll-ethyl ester, m.p. 8l82 yield 70 percent of theoretical value.

b. 76 g. of this acetic acid ester, dissolved with l l g. of sodium hydroxide, are hydrolyzed in 270 ml. of 50 percent ethanol. After cooling of the reaction mixture and addition of water, 66 g. of crystallized 2-( p-isopropoxybenzoyl)-5-methyl- 3-benzofuranethanol, m.p. ll4-l are obtained, yield 97 percent of theoretical value.

c. 66 g. of 2-(p-isopropoxybenzoyl)-5-methyl-3-benzofuranethanol are reacted with 122 g. of p-toluenesulfochloride. After crystallization from ether are obtained 79 g. of ptoluenesulfonic acid-2-[2-(p-isopropoxybenzoyl)-5-methyl-3- benzofuranyl1-ethyl ester, m.p. 93-94; yield 82 percent of theoretical value.

From 6.0 g. of this p-toluenesulfonic acid ester and 30 ml. of morpholine is obtained the 4-[2-[2-(p-isopropoxybenzoyl)-5- methyl-3-benzofuranyl]-ethyl]morpholine. The hydrochloride of the latter melts, after recrystallization from acetone/ether, at 220-222; yield 5.0 g., 92 percent of theoretical value.

d. From 9.0 g. of the p-toluenesulfonic acid ester obtained in (c) and 45 ml. of pyrrolidine is obtained the 1-[2-[2-(pisopropoxybenzoyl)-5-methyl-3-benzofuranyl]-ethyl]-pyrrolidine, the hydrochloride of which melts, after recrystallization from acetone/ether, at l92l94; yield 7.5 g., 96 percent of theoretical value.

From 5.0 g. of the p-toluenesulfonic acid ester obtained in (c) and ml. of piperidine is obtained the l-[2-[2-(pisopropoxybenzoyl)-5-methyl-3-benzofuranyl]-ethy1]- piperidine. The hydrochloride of the latter melts, after recrystallization from acetone/ether, at 207-208; yield 3.88 g., 90 percent of theoretical value.

e. Analogously to example 34 are obtained from 5.0 g. of 4- [2-[2-(p-isopropoxybenzoyl)-5-methyl-3-benzofuranyl1- ethyl]-morpholine, after conversion into the free base and reduction of the latter with 20 ml. of hydrazine hydrate, the 4- [2-[2-(p-isopropoxybenzyl)-5-methyl-3-benzofuranyl]-ethyl]- morpholine. The hydrochloride of the latter melts, after recrystallization from acetone/ether, at 199200; yield 3.6 g., 68 percent of theoretical value.

di-n-pripylamine are obtained, after crystallization from acetone/ether, 1.1 g. of N,N-dipropyl-2-[2-(p-isopropoxybenzoyl)-5-methyl-3-benzofuranyl] ethylamine hydrochloride, m.p. 198l99; yield 45 percent of theoretical value.

f. 1.0 g. of N,N-dipropyl-2-[2-(p-isopropoxybenzoyl)-5- methyl-3-benzofuranyl]-ethylamine hydrochloride is treated with 4.5 ml. of hydrazine hydrate in 20 ml. of diethylene glycol and 2.2 g. of potassium hydroxide. After crystallization from acetone are obtained 3.78 g. of N,N-dipropyl-2-[2-(pisopropoxybenzyl)-5-methyl-3-benzofuranyl]-ethylamine hydrochloride, m.p. 163-164; yield 80 percent of theoretical value.

EXAMPLE 40 a. 3.6 g. of 2-(p-ethoxybenzyl)-2,3-dihydro-3-hydroxy-5- methyl-3-benzofuranacetic acid methyl ester (mixture of the isomeric hydroxy esters) are added to a suspension of 1.5 g. of lithium aluminum hydride in 30 ml. of tetrahydrofuran. The mixture is refluxed to boiling, while stirring, for 3 hours. It is then allowed to cool and 60 ml. of ether are added. The mixture is decomposed by slowly adding dropwise 1.75 ml. of water, 1.25 ml. of concentrated sodium hydroxide solution and 5.25 ml. of water. After decanting the precipitate, washing it with ether and concentrating the organic solutions by,

evaporation, an oily product is obtained, which is taken up in ether. The ethereal solution is washed with water, dried over sodium sulfate and concentrated by evaporation in vacuo. The oil remaining yields, from ether/petroleum ether, 1.3 g. of 2- (p-ethoxybenzyl)-2,3-dihydro-3-hydroxy-5-methyl-3- benzofuranethanol, m.p. 98-99; yield 39 percent of theoretical value.

b. 0.7 g. of the alcohol, obtained according to (a), are reacted with 1.5 g. of p-toluenesulfochloride in 8 ml. of absolute pyridine. After completion of the reaction, the mixture is poured into ice water and the precipitated oil taken up in ether. The ethereal solution is separated, by washing with 0.2N sulfuric acid, from adhering pyridine. it is then washed with water, dried over sodium sulfate and concentrated by evaporation in vacuo at 20. The obtained oil yields, from ether/petroleum ether, 0.95 g. of p-toluenesulfonic acid-2-[2- (p-ethoxybenzyl)-2,3-dihydro-3hydroxy-5-methyl-3- benzofuranyl1-ethyl ester, m.p. 74-75 (decomposition); yield 87 percent of theoretical value.

c. 0.20 g. of the p-toluenesulfonic acid ester, obtained according to (b), are reacted with 1 ml. of pyrrolidine or piperidine. After recrystallization from acetone/ether are obtained 0.12 g. of l-[2-[2-(p-ethoxybenzyl)-5-methyl-3- benzofuranyl]-ethyl]-pyrrolidine hydrochloride (yield 69 percent of theoretical value), m.p. l67-l69, or 0.1 l g. of l-[2- [2-(p-ethoxybenzyl)-5-methyl-3-benz0furanyl]-ethyl]- piperidine hydrochloride, m.p. 198-193 (yield 61 percent of theoretical value), respectively.

In an analogous manner, 0.2 g. of the p-toluene-sulfonic acid ester, obtained according to (b), are reacted with 1 ml. of di-n-propylamine. After crystallization from acetone/ether, 0.1 g. of N,N-dipropyl-2-(p-ethoxybenzyl)-5-methyl-3- 

2. A compound according to claim 1 wherein R1 is hydrogen or methyl; R2 is chloro, methyl or ethyl; R3 is ethyl or isopropyl; and each of R4 and R5 independent of the other is ethyl or propyl, or together with the adjacent nitrogen form the 1-pyrrolidinyl, piperidino or morpholino group.
 3. A compound according to claim 1 which is 1-(2-(2-(p-ethoxybenzyl)-5-methyl-3-benzofuranyl)-ethyl)-pyrrolidine.
 4. A compound according to claim 1 which is 1-(2-(2-(p-ethoxybenzyl)-5,6-dimethyl-3-benzofuranyl)-ethyl)-pyrrolidine.
 5. A compound according to claim 1 which is N,N-diethyl-2-(p-ethoxybenzyl)-6-methyl-3-benzofuranethylamine.
 6. A compound according to claim 1 which is 1-(2-(2-(p-ethoxybenzyl)-5-methyl-3-benzofuranyl)-ethyl)-piperidine.
 7. A compound according to claim 1 which is 4-(2-(2-(p-isopropoxybenzyl)-5-methyl-3-benzofuranyl)-ethyl)-morpholine.
 8. A compound according to claim 1 which is 1-(2-(2-(p-ethoxybenzyl)-5-chloro-3-benzofuranyl)-ethyl)-pyrrolidine.
 9. A compound according to claim 1 which is N,N-diethyl-2-(p-ethoxybenzyl)-5-methoxy-3-benzofuranethylamine.
 10. A compound according to claim 1 which is N,N-di-n-propyl-(p-ethoxybenzyl)-5-methyl-3-benzofuranethylamine.
 11. A compound according to claim 1 which is 1-(2-(2-(p-isopropoxybenzyl)-5-methyl-3-benzofuranyl)-ethyl)-piperidine.
 12. A compound according to claim 1 which is 1-(2-(2-(p-isopropoxybenzyl)-5-methyl-3-benzofuranyl)-ethyl)-pyrrolidine.
 13. A compound according to claim 1 which is 1-(2-(2-(p-ethoxybenzyl)-6-methyl-3-benzofuranyl)-ethyl)-pyrrolidine.
 14. A compound according to claim 1 which is 1-(2-(2-(p-ethoxybenzyl)-6-ethyl-3-benzofuranyl)-ethyl)-pyrrolidine.
 15. A compound according to claim 1 which is N,N-diethyl-2-(p-ethoxybenzyl)-5-chloro-3-benzofuranethylamine.
 16. A compound according to claim 1 which is 1-(2-(2-(p-ethoxybenzyl)-3-benzofuranyl)-ethyl)-piperidine.
 17. A compound according to claim 1 which is 4-(2-(2-(p-ethoxybenzyl)-3-benzofuranyl)-eThyl)-morpholine. 